Prodrugs of NH-acidic compounds

ABSTRACT

The invention provides a method of sustained delivery of a lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug by administering to a patient an effective amount of a prodrug compound of the invention wherein upon administration to the patient, release of the parent drug from the prodrug is sustained release. Prodrug compounds suitable for use in the methods of the invention are labile conjugates of parent drugs that are derivatized through carbonyl linked prodrug moieties. The prodrug compounds of the invention can be used to treat any condition for which the lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug is useful as a treatment.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/755,412, filed Jun. 30, 2015, which is a divisional of U.S.application Ser. No. 14/172,391, filed on Feb. 4, 2014, now U.S. Pat.No. 9,102,618, which is a continuation of U.S. application Ser. No.12/823,102, filed on Jun. 24, 2010, now U.S. Pat. No. 8,686,009, whichclaims the benefit of U.S. Provisional Application No. 61/220,480, filedon Jun. 25, 2009; 61/293,087, filed on Jan. 7, 2010; and 61/293,133,filed on Jan. 7, 2010. The entire teachings of the above applicationsare incorporated herein by reference.

BACKGROUND OF THE INVENTION

(i) Field of the Invention

The present invention relates to prodrugs of lactam, amide, imide,sulfonamide, carbamate, urea, benzamide, and acylaniline containingpharmacophores.

(ii) Background of the Invention

Drug delivery systems are often critical for the safe and effectiveadministration of a biologically active agent. Perhaps the importance ofthese systems is best realized when patient compliance and consistentdosing are taken under consideration. For instance, reducing the dosingrequirement for a drug from four-times-a-day to a single dose per daywould have significant value in terms of ensuring patient compliance andoptimizing therapy.

Optimization of a drug's bioavailability has many potential benefits.For patient convenience and enhanced compliance it is generallyrecognized that less frequent dosing is desirable. By extending theperiod through which the drug is released, a longer duration of actionper dose is expected. This will then lead to an overall improvement ofdosing parameters such as taking a drug once a day where it haspreviously required four doses per day or dosing once a week or evenless frequently when daily dosing was previously required. Many drugsare presently dosed once per day, but not all of these drugs havepharmacokinetic properties that are suitable for dosing intervals ofexactly twenty-four hours. Extending the period through which thesedrugs are released would also be beneficial.

One of the fundamental considerations in drug therapy involves therelationship between blood levels and therapeutic activity. For mostdrugs, it is of primary importance that serum levels remain between aminimally effective concentration and a potentially toxic level. Inpharmacokinetic terms, the peaks and troughs of a drug's blood levelsideally fit well within the therapeutic window of serum concentrations.For certain therapeutic agents, this window is so narrow that dosageformulation becomes critical.

In an attempt to address the need for improved bioavailability, severaldrug release modulation technologies have been developed. For example,poorly soluble 5,5 diphenylimidazolidine-2,4-diones have beenderivatized into phosphate ester prodrugs to improve solubility. (Stellaet. al., U.S. Pat. No. 4,260,769, 1981). Enteric coatings have been usedas a protector of pharmaceuticals in the stomach and microencapsulatingactive agents using proteinaceous microspheres, liposomes orpolysaccharides have been effective in abating enzymatic degradation ofthe active agent. Enzyme inhibiting adjuvants have also been used toprevent enzymatic degradation.

A wide range of pharmaceutical formulations provide sustained releasethrough microencapsulation of the active agent in amides of dicarboxylicacids, modified amino acids or thermally condensed amino acids. Slowrelease rendering additives can also be intermixed with a large array ofactive agents in tablet formulations.

While microencapsulation and enteric coating technologies impartenhanced stability and time-release properties to active agentsubstances these technologies suffer from several shortcomings.Incorporation of the active agent is often dependent on diffusion intothe microencapsulating matrix, which may not be quantitative and maycomplicate dosage reproducibility. In addition, encapsulated drugs relyon diffusion out of the matrix or degradation of the matrix, or both,which is highly dependent on the chemical properties and watersolubility of the active agent. Conversely, water-soluble microspheresswell by an infinite degree and, unfortunately, may release the activeagent in bursts with limited active agent available for sustainedrelease. Furthermore, in some technologies, control of the degradationprocess required for active agent release is unreliable. For example,because an enterically coated active agent depends on pH to release theactive agent and pH and residence time varies, the release rate isdifficult to control.

Several implantable drug delivery systems have utilized polypeptideattachment to drugs. Additionally, other large polymeric carriersincorporating drugs into their matrices are used as implants for thegradual release of drug. Yet another technology combines the advantagesof covalent drug attachment with liposome formation where the activeingredient is attached to highly ordered lipid films.

However, there is still a need for an active agent delivery system thatis able to deliver certain active agents which have been heretofore notformulated or difficult to formulate in a sustained release formulationfor release over a sustained period of time and which is convenient forpatient dosing.

There is a generally recognized need for sustained delivery of drugsthat reduces the daily dosing requirement and allows for controlled andsustained release of the parent drug and also avoids irregularities ofrelease and cumbersome formulations encountered with typical dissolutioncontrolled sustained release methods.

SUMMARY OF THE INVENTION

The present invention accomplishes this by extending the period duringwhich a lactam, amide, imide, sulfonamide, carbamate, urea, benzamide,acylaniline, and cyclic amide containing parent drug is released andabsorbed after administration to the patient and providing a longerduration of action per dose than the parent drug itself. In oneembodiment, the compounds suitable for use in the methods of theinvention are derivatives of lactam-, amide-, imide-, sulfonamide-,carbamate-, urea-, benzamide-, acylaniline-, and cyclic amide-containingparent drugs that are substituted at the amide nitrogen or oxygen atomwith labile aldehyde-linked prodrug moieties. Preferably, the prodrugmoieties are hydrophobic and reduce the polarity and solubility of theparent drug under physiological conditions.

In one embodiment, the invention provides a prodrug compound of FormulaI, II or III:

and the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof;wherein A and B together with the —N(C═X)— or —N═C—X— or —S(O)₂—N— groupto which they are attached form a parent drug;X is —S— or —O—;R₁ is selected from —C(R_(A))(R_(B))—OR₂₀, —C(R_(A))(R_(B))—OC(O)OR₂₀,—C(R_(A))(R_(B))—OC(O)R₂₀, —C(R_(A))(R_(B))—OC(O)NR₂₀R₂₁,—(C(R_(A))(R_(B)))—OPO₃MY, —(C(R_(A))(R_(B)))—OP(O)(OR₂₀)(OR₂₁),—[C(R_(A))(R_(B))O]_(z)—R₂₀, —[C(R_(A))(R_(B))O]_(z)—C(O)OR₂₀,—[C(R_(A))(R_(B))O]_(z)—C(O)R₂₀, —[C(R_(A))(R_(B))O]_(z)—C(O)NR₂₀R₂₁,—[C(R_(A))(R_(B))O]_(z)—OPO₃MY, —[C(R_(A))(R_(B))O]_(z)—P(O)₂(OR₂₀)M and—[C(R_(A))(R_(B))O]_(z)—P(O)(OR₂₀)(OR₂₁);

-   -   wherein z is 2 or 3;    -   wherein each R_(A) and R_(B) is independently selected from        hydrogen, halogen, aliphatic, substituted aliphatic, aryl or        substituted aryl;    -   each R₂₀ and R₂₁ is independently selected from hydrogen,        aliphatic, substituted aliphatic, aryl or substituted aryl;    -   Y and M are the same or different and each is a monovalent        cation; or M and Y together is a divalent cation, and,    -   wherein when said parent drug contains a 5,5        diphenylimidazolidine-2,4-dione moiety of formula I, R₁ is other        than —CH(R_(A))OPO₃MY, CH(R_(A))OP(O)(OH)₂, or        —CH(R_(A))OC(O)R₂₀.

The invention further provides a method for sustained delivery of aparent drug by the administration of a conjugate of the parent drug witha labile moiety, wherein the conjugate is represented by formula I, IIor III.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

FIG. 1: PXRD spectrum of Compound-7

FIG. 2: IR Spectrum of Compound-7

FIG. 3: Raman spectrum of Compound-7

FIG. 4: TGA thermogram of Compound-7

FIG. 5: DSC thermogram of Compound-7

FIG. 6: Pharmacodynamic (PD) study of compound-4 in AMPH inducedlocomotion model.

FIG. 7: Pharmacodynamic (PD) study of compound-7 in AMPH inducedlocomotion model.

FIG. 8: Plasma concentration of aripiprazole after intravenousadministration of (0.5 mg/Kg) compound 7 to rats.

FIG. 9: Plasma concentration of aripiprazole, dehydroaripiprazole andcompound 7 after intramuscular administration of 30 mg/kg of compound 7to dogs.

FIG. 10: Pharmacokinetic profile of pioglitazone, Compound-1002 andCompound-1008 after intravenous administration (20 mg pioglitazoneequivalent) to rats.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention provides a compound having thegeneral formula I, II or III:

or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof;

-   -   wherein A and B together with the —N(C═X)— or —N═C—X— or        —S(O)₂—N— they are attached forms a parent drug;    -   X is —S— or —O—;        R₁ is selected from —C(R_(A))(R_(B))—OR₂₀,        —C(R_(A))(R_(B))—OC(O)OR₂₀, —C(R_(A))(R_(B))—OC(O)R₂₀,        —C(R_(A))(R_(B))—OC(O)NR₂₀R₂₁, —(C(R_(A))(R_(B)))—OPO₃MY,        —(C(R_(A))(R_(B)))—OP(O)(OR₂₀)(OR₂₁),        —[C(R_(A))(R_(B))O]_(z)—R₂₀, —[C(R_(A))(R_(B))O]_(z)—C(O)OR₂₀,        —[C(R_(A))(R_(B))O]_(z)—C(O)R₂₀,        —[C(R_(A))(R_(B))O]_(z)—C(O)NR₂₀R₂₁,        —[C(R_(A))(R_(B))O]_(z)—OPO₃MY,        —[C(R_(A))(R_(B))O]_(z)—P(O)₂(OR₂₀)M and        —[C(R_(A))(R_(B))O]_(z)—P(O)(OR₂₀)(OR₂₁);    -   wherein each R_(A) and R_(B) is independently selected from        hydrogen, halogen, aliphatic, substituted aliphatic, aryl or        substituted aryl;    -   each R₂₀ and R₂₁ is independently selected from hydrogen,        aliphatic, substituted aliphatic, aryl or substituted aryl;    -   Y and M are the same or different and each is a monovalent        cation; or M and Y together is a divalent cation; and,    -   wherein when said parent drug contains a 5,5        diphenylimidazolidine-2,4-dione moiety of formula I, R₁ is other        than —CH(R_(A))OPO₃MY, CH(R_(A))OP(O)(OH)₂, or        —CH(R_(A))OC(O)R₂₀.

In one embodiment, the compounds of the invention having Formulas I, IIand III are less soluble, and are preferably at least an order ofmagnitude less soluble, as compared to the parent drug from which theywere derived. In one embodiment, the prodrugs of Formulas I, II and IIIhave an aqueous solubility of less than about 0.5 mg/ml, preferably lessthan about 0.1 mg/mL, preferably less than about 0.01 mg/mL, preferablyless than about 0.001 mg/mL, preferably less than about 0.0001 mg/mL andeven more preferably less than about 0.00001 mg/ml when solubility ismeasured in a phosphate buffer (pH 7.4) at room temperature.

In a preferred embodiment, a compound of the invention providessustained delivery of the parent drug over hours, days, weeks or monthswhen administered, for example, orally or parenterally, to a subject.For example, the compounds can provide sustained delivery of the parentdrug for at least 8, 12, 24, 36 or 48 hours or at least 4, 7, 15, 30,60, 75 or 90 days or longer. Without being bound by a theory, it isbelieved that the compounds of the invention form an insoluble depotupon parenteral administration, for example subcutaneous, intramuscularor intraperitoneal injection. In one embodiment a prodrug of theinvention may further comprise a sustained release delivery system forproviding additional protection of the prodrug from enzymatic orchemical degradation.

In another embodiment, the invention provides a method for sustaineddelivery of a parent lactam, amide, imide, sulfonamide, carbamate, urea,benzamide, or acylaniline containing drug to a subject in need thereof.Each of these groups comprises an amidic N—H group. The method comprisesadministering to the subject an effective amount of a prodrug formed bysubstituting on the NH group a labile, hydrophobic aldehyde-linkedprodrug moiety wherein the prodrug has reduced solubility underphysiological conditions compared to the parent drug and provides forlonger sustained therapeutic levels of the parent drug followingadministration than observed levels following administration of theparent drug. In a preferred embodiment, the amidic N—H group has a pKaof about 5 to about 22, preferably about 5 to about 21, and preferablyabout 5 to about 20.

In a preferred embodiment, R₁ is selected from Table-1.

TABLE 1

In a more preferred embodiment, R₁ is selected from Table 2.

TABLE 2

In a more preferred embodiment, R₁ is selected from Table 3.

TABLE 3

In a more preferred embodiment, R₁ is selected from Table 4.

TABLE 4

Prodrugs of Lactam, Cyclic Urea, Imide, Carbamate ContainingPharmacophores

In one embodiment, compounds of the present invention are represented byformula IV or V as illustrated below, or its geometric isomers,enantiomers, diastereomers, racemates, pharmaceutically acceptable saltsco-crystals and solvates thereof:

wherein

represents a single or double bond;X and R₁ are as defined above;each X₁, X₂, and X₃ is independently selected from absent, —S—, —O—,—S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—, —C(OR₁₀)(R₁₁)—, —[C(R₁₀)(R₁₁)]_(v)—,—C(R₁₀)═C(R₁₀)—; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

-   -   wherein each R₁₀ and R₁₁ is independently absent, hydrogen,        halogen, aliphatic, substituted aliphatic, aryl or substituted        aryl; alternatively, two R₁₀ and R₁₁ together with the atoms to        which they are attached may form an additional optionally        substituted, 3, 4, 5, 6 or 7 membered ring; and        t is 0, 1, 2 or 3.

In one embodiment, compounds of the present invention are represented byformula VI or VII as illustrated below, and the geometric isomers,enantiomers, diastereomers, racemates, pharmaceutically acceptable saltsand solvates thereof:

wherein

represents a single or double bond;X, X₁, X₂ and R₁ are as defined above;ring Y is an optionally substituted cycloalkyl, cycloalkenyl,heterocyclyl or aryl containing one, two or three rings;each F₁ and F₂ is independently selected from absent and R₅-A-Cy₁-B-D-;

-   -   wherein, A is selected from absent, optionally substituted        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, —S—, —O—, —S(O)—, —S(O)₂—, —S[C(R₃₀)(R₃₁)]_(u)—,        —S(O)[C(R₃₀)(R₃₁)]_(u)—, —S(O)₂[C(R₃₀)(R₃₁)]_(u)—,        —O[C(R₃₀)(R₃₁)]_(u)—, —N(R₃₀)—, —N(R₃₀)[C(R₃₁)(R₃₂)]_(u)—,        —[C(R₃₀)(R₃₁)]_(u)—, —C(O)[C(R₃₀)(R₃₁)]_(u)—;    -   wherein each u is independently 1, 2, 3, 4, 5, 6 or 7;    -   Cy₁ is absent or an optionally substituted cycloalkyl,        optionally substituted cycloalkenyl, optionally substituted        heterocyclyl, optionally substituted aryl or optionally        substituted heteroaryl;    -   B is absent, or a linker;    -   D is selected from absent, —O—, —NR₃₃, —C(R₃₄)(R₃₅)—, —S—,        —S(O)—, —S(O)₂—, and —C(O)—;        each G₁ and G₂ is independently selected from absent, —S—, —O—,        —S(O)—, —S(O)₂—, —SC(R₄₀)(R₄₁)—, —S(O) C(R₄₀)(R₄₁)—,        —S(O)₂C(R₄₀)(R₄₁)—, —C(O)—, —C(OR₄₀)(R₄₁)—, —OC(R₄₀)(R₄₁)—,        —N(R₄₀)—, —C(R₄₀)═C(R₄₁)—, —N(R₄₀)—C(R₄₁)(R₄₂)—, and        —[C(R₄₀)(R₄₁)]_(u)—;        each R₃, R₄, R₅, R₃₀, R₃₁, R₃₂ R₃₃, R₃₄, R₃₅, R₄₀, R₄₁, and R₄₂        is independently selected from absent, hydrogen, halogen, —OR₁₀,        —SR₁₀, —NR₁₀R₁₁—, —C(O)R₁₀, optionally substituted aliphatic,        optionally substituted aryl or optionally substituted        heterocyclyl;        alternatively, two R₃ groups or two R₄ groups or one R₃ group        with one R₄ group together with the atoms to which they are        attached and any intervening atoms form an optionally        substituted ring;        m and q are independently selected from 0, 1, and 2.

In a preferred embodiment, G₂ is selected from —N— or —C(R₁₀)—.

In a preferred embodiment, the R₅ moiety is an aryl or heteroaryl groupselected from:

wherein R₁₀₀ and R₁₀₁, each represent 1 to 4 substituents independentlyselected from hydrogen, halogen, optionally substituted C₁-C₈ alkyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₃-C₅ cycloalkyl, optionally substitutedC₁-C₈ alkoxy, optionally substituted C₁-C₈ alkylamino and optionallysubstituted C₁-C₈ aryl; and, R₁₀₃ is selected from hydrogen, halogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₁-C₈ alkoxy, optionallysubstituted C₁-C₅ alkylamino and optionally substituted C₁-C₅ aryl.

In a preferred embodiment, Cy₁ is selected from:

In a preferred embodiment, the bivalent B is a direct bond, a straightchain C₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl, C₁-C₁₀ alkoxy,alkoxyC₁-C₁₀alkoxy, C₁-C₁₀ alkylamino, alkoxyC₁-C₁₀alkylamino, C₁-C₁₀alkylcarbonylamino, C₁-C₁₀ alkylaminocarbonyl, aryloxyC₁-C₁₀alkoxy,aryloxyC₁-C₁₀alkylamino, aryloxyC₁-C₁₀alkylamino carbonyl,C₁-C₁₀-alkylaminoalkylaminocarbonyl, C₁-C₁₀alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino,alkylcarbonylaminoalkylamino, alkyl(N-alkyl)aminoalkylamino,(N-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl,alkylaminoalkylaminoalkyl, alkylpiperazinoalkyl, piperazinoalkyl,alkylpiperazino, alkenylaryloxyC₁-C₁₀alkoxy,alkenylarylaminoC₁-C₁₀alkoxy, alkenylaryllalkylaminoC₁-C₁₀alkoxy,alkenylaryloxyC₁-C₁₀alkylamino, alkenylaryloxyC₁-C₁₀alkylaminocarbonyl,piperazinoalkylaryl, heteroarylC₁-C₁₀alkyl, heteroarylC₂-C₁₀ alkenyl,heteroarylC₂-C₁₀ alkynyl, heteroarylC₁-C₁₀alkylamino,heteroarylC₁-C₁₀alkoxy, heteroaryloxyC₁-C₁₀alkyl, heteroaryloxyC₂-C₁₀alkenyl, heteroaryloxyC₂-C₁₀ alkynyl, heteroaryloxyC₁-C₁₀alkylamino orheteroaryloxyC₁-C₁₀alkoxy.

In one embodiment, compounds of the present invention are represented byformula VIII or VIIIA as illustrated below, and the geometric isomers,enantiomers, diastereomers, racemates, pharmaceutically acceptable saltsand solvates thereof:

wherein Ring Y, R₁, R₃, R₄, G₁, G₂, X, F₂, m and q are as defined above.

In a more preferred embodiment, compounds of the present invention arerepresented by formula IX or X as illustrated below, and the geometricisomers, enantiomers, diastereomers, racemates, pharmaceuticallyacceptable salts and solvates thereof:

wherein R₁, R₃, F₂, and q are as defined above.

In a preferred embodiment a compound is selected from Table IX-X. A morepreferred embodiment is a compound from Table IX-X wherein R₁ isselected from tables 1-4.

TABLE IX-X No Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

In a more preferred embodiment, prodrugs of domperidone are disclosed.(Formula 4 and 11 from Table IX-X). A more preferred embodiment is acompound of Formula 4 from Table IX-X, wherein R₁ is selected fromtable 1. In a more preferred embodiment, a compound of Formula 4 fromTable IX-X, wherein R₁ is selected from tables 2-4 is disclosed.

In a more preferred embodiment, prodrugs of droperidol are disclosed.(Formula 6 and 13, from Table IX-X). In a more preferred embodiment, acompound of Formula 6 from Table IX-X wherein R₁ is selected from table1 is disclosed. A more preferred embodiment is a compound of Formula 6from Table IX-X wherein R₁ is selected from tables 2-4.

In a more preferred embodiment, prodrugs of pimozide are disclosed.(Formula 7 and 14 from Table IX-X). In a more preferred embodiment, acompound of Formula 7 from Table IX-X wherein R₁ is selected from table1 is disclosed. In a more preferred embodiment, a compound of Formula 7from Table IX-X wherein R₁ is selected from tables 2-4 is disclosed.

In another embodiment, compounds of the present invention arerepresented by Formula XI or XII as illustrated below, and the geometricisomers, enantiomers, diastereomers, racemates, pharmaceuticallyacceptable salts and solvates thereof:

wherein Ring Y, R₁, R₃, R₄, X, F₁, G₁, G₂, m and q are as defined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIA or XIIA as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, R₃, R₄, R₅, R₁₀, R₁₁, A, D, m, and q are as defined above;R₂ is selected from absent, hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—,optionally substituted aliphatic, optionally substituted aryl or aryl oroptionally substituted heterocyclyl;r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;each G₃ and G₄ is independently selected from —N—, and—C(R₁₀)—[C(R₁₀)(R₁₁)]_(a)—, wherein a is 0, 1 or 2;X₂₀ is —C(R₁₀)— or —N—; and,p is 0, 1, 2 or 3.

In another embodiment, compounds of the present invention arerepresented by Formula XIB or XIIB as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof

wherein R₁, R₂, R₃, R₄, R₅, R₁₀, R₁₁, A, D, m, p and q are as definedabove.

In another embodiment, compounds of the present invention arerepresented by Formula XIC or XIIC as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, is as defined above; and,w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

In another embodiment, compounds of the present invention arerepresented by Formula XID or XIID as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X₁, R₁, R₂, R₃, R₅, A, B, D, G₃, G₄, p, q, R₁₀ and R₁₁ are asdefined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIE or XIIE as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X, R₁, R₂, R₃, R₄, A, D, G₃, G₄, m, q, r, R₁₀ and R₁₁ are asdefined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIF or XIIF as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X, R₁, R₂, D, r, R₁₀ and R₁₁ are as defined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIG or XIIG as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, is as defined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIH or XIIH as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X, R₁, R₂, R₅, A, D, G₃, G₄ and p, are as defined above.

In another embodiment, compounds of the present invention arerepresented by Formula XI-I or XII-I as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, is as defined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIJ or XIIJ as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X, R₁, R₂, R₃, R₄, R₅, A, D, G₃, G₄, p, R₁₀ and R₁₁ are asdefined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIK or XIIK as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, is as defined above.

In a preferred embodiment a compound is selected from Table XI-XII. Amore preferred embodiment is a compound from Table XI-XII wherein R₁ isselected from Table 1-4.

TABLE XI-XII 1

2

3

4

5

6

7

8

9

10

11

12

In a more preferred embodiment, prodrugs of aripiprazole are disclosed.(Formula 1 and 7 from Table XI-XII). In a more preferred embodiment, acompound of Formula 1 wherein R₁ is selected from table 1 is disclosed.In a more preferred embodiment, a compound of Formula 1 wherein R₁ isselected from tables 2-4 is disclosed.

In a more preferred embodiment, prodrugs of dehydroaripiprazole aredisclosed. (Formula 2 and 8 from Table XI-XII). In a more preferredembodiment, a compound of Formula 2 wherein R₁ is selected from table 1is disclosed. In a more preferred embodiment, a compound of Formula 2wherein R₁ is selected from tables 2-4 is disclosed.

In a more preferred embodiment, prodrugs of ziprasidone are disclosed.(Formula 3 and 9 from Table XI-XII). In a more preferred embodiment, acompound of Formula 3 wherein R₁ is selected from table 1 is disclosed.In a more preferred embodiment, a compound of Formula 3 wherein R₁ isselected from tables 2-4 is disclosed.

In a more preferred embodiment, prodrugs of bifeprunox are disclosed.(Formula 4 and 11 from Table XI-XII). In a more preferred embodiment, acompound of Formula 4 wherein R₁ is selected from table 1 is disclosed.In a more preferred embodiment, a compound of Formula 4 wherein R₁ isselected from tables 2-4 is disclosed.

Representative compounds according to the invention are those selectedfrom the Tables A-I below and the geometric isomers, enantiomers,diastereomers, racemates, pharmaceutically acceptable salts and solvatesthereof:

TABLE A No Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

TABLE B No Structure 150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

TABLE C No. Structure 400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

TABLE D No. Structure 501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

In another embodiment, the invention relates to a compound of formula LIand LII:

In another aspect of the invention, compounds of formula LI and LII areselected from Table E and F:

TABLE E No Structure 700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

744

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

TABLE F No Structure 900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936

937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

Compounds of formula IX, X, XI, XII and in particular compounds oftables A-D are useful for the treatment of neurological and psychiatricdisorders including schizophrenia, mania, anxiety and bipolar disease.These compounds provide sustained release of parent pharmacophores bycleavage of the labile moiety, R₁. As such, the compounds of formula IX,X, XI, XII and in particular compounds of tables A-D are useful for thetreatment of neurological disorders by providing sustained release ofparent drugs.

In another embodiment, compounds of the present invention arerepresented by formula XIII or XIV as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁₀₀, R₁₀₁, R₁₀₂, and R₁₀₃ are independently selected fromabsent, hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, optionallysubstituted aliphatic, optionally substituted aryl or aryl or optionallysubstituted heterocyclyl;alternatively, two R₁₀₀, and R₁₀₁ together with the atoms they areattached and any intervening atoms form an optionally substituted ring;and,X₁₀₀ is —CH— or —N—.

A preferred embodiment is a compound selected from Table XIII-XIV. Amore preferred embodiment is a compound from Table XIII-XIV wherein R₁is selected from tables 1-4.

TABLE XIII-XIV  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

Prodrugs of Acylanilines

In another embodiment, compounds of the present invention arerepresented by formula XV or XVI as illustrated below, or its geometricisomers, enantiomers, diastereomers, racemates, pharmaceuticallyacceptable salts and solvates thereof:

wherein R₁ is as defined above;each R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ is independently selected fromhydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, optionally substitutedaliphatic, optionally substituted aryl or aryl or optionally substitutedheterocyclyl;alternatively, two or more R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ together withthe atoms to which they are attached form an optionally substitutedring.

A preferred embodiment is a compound selected from Table XV-XVI. A morepreferred embodiment is a compound from Table XV-XVI wherein R₁ isselected from tables 1-4.

TABLE XV-XVI   1 

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

Thiazolidinones

In another embodiment, compounds of the present invention arerepresented by formula XVII, XVIII or XIX as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein F₁ and R₁ are as defined above.

A preferred embodiment is a compound of formula XX, XXI or XXII asillustrated below, and the geometric isomers, enantiomers,diastereomers, racemates, pharmaceutically acceptable salts and solvatesthereof:

wherein R₁ is as defined above;Cy₂ is an optionally substituted heterocyclic ring; and,X₅ is selected from absent, —S—, —O—, —S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—,—[C(R₁₀)(R₁₁)]_(v)—, —O[C(R₁₀)(R₁₁)]_(v)—, —O[C(R₁₀)(R₁₁)]_(v)O—,—S[C(R₁₀)(R₁₁)]_(v)O—, —NR₁₂[C(R₁₀)(R₁₁)]_(v)O—,—NR₁₂[C(R₁₀)(R₁₁)]_(v)S—, —S[C(R₁₀)(R₁₁)]_(v)—, —C(O)[C(R₁₀)(R₁₁)]_(v)—,and —C(R₁₀)═C(R₁₀)—; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

A preferred embodiment is a compound of formula XXIV as illustratedbelow, and the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of formula XXIV, R₁ is selected fromtables 1-4.

A preferred embodiment is a compound of formula XXV as illustratedbelow, and the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of formula XXV, R₁ is selected fromtables 1-4.

A preferred embodiment is a compound of formula XXVI as illustratedbelow, and the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of formula XXVI, R₁ is selected fromtables 1-4.

A preferred embodiment is a compound of formula XXVII as illustratedbelow, and the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of formula XXVII, R₁ is selected fromtables 1-4.

A preferred embodiment is a compound of formula XXVIII as illustratedbelow, and the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of formula XXVIII, R₁ is selected fromtables 1-4.

A preferred embodiment is a compound of formula XXIX as illustratedbelow, and the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of formula XXIX, R₁ is selected fromtables 1-4.

A preferred embodiment is a compound of formula XXX as illustratedbelow, and the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of formula XXX, R₁ is selected from Table1.

A preferred embodiment is a compound of formula XXXI as illustratedbelow, and the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of formula XXXI, R₁ is selected fromTable 1.

A preferred embodiment is a compound of formula XXXII as illustratedbelow, and the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of formula XXXII, R₁ is selected fromTable 1.

In a preferred embodiment a compound of formula XX-XXII is selected fromtable XX-XXII below, wherein R₁ is as described above. A more preferredembodiment is a compound of table XX-XXII wherein R₁ is selected fromtables 1-4.

TABLE XX-XXII  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

Thiazolidinedione prodrugs of formula XVII to XXXII are useful for thetreatment of type 2 diabetes mellitus. Herein provided is a method oftreating type 2 diabetes mellitus by the administration of a prodrug offormula XVII to XXXII, in particular a compound of table XX-XXII abovewherein the prodrug provides sustained release of the parent drug. Theparent drug results from the cleavage of the labile R₁ moiety.

In some embodiments, a compound of formula XXVII is selected from TableG:

TABLE G No. Structure 1000.

1001.

1002.

1003.

1004.

1005.

1006.

1007.

1008.

1009.

1010.

1011.

1012.

1013.

1014.

1015.

1016.

1017.

1018.

1019.

1020.

1021.

1022.

1023.

1024.

1025.

1026.

1027.

1028.

1029.

1030.

1031.

1032.

1033.

1034.

1035.

1036.

1037.

1038.

1039.

1040.

1041.

TABLE H No Structure 1100.

1101.

1102.

1103.

1104.

1105.

1106.

1107.

1108.

1109.

1110.

1111.

1112.

1113.

1114.

1115.

1116.

1117.

1118.

1119.

1120.

1121.

1122.

1123.

1124.

1125.

1126.

1127.

1128.

1129.

1130.

1131.

1132.

1133.

1134.

1135.

1136.

1137.

1138.

1139.

1140.

1141.

1142.

1143.

1144.

1145.

1146.

1147.

1148.

1149.

1150.

1151.

1152.

1153.

1154.

1155.

1156.

1157.

1158.

1159.

1160.

1161.

1162.

1163.

1164.

1165.

1166.

1167.

TABLE I No Structure 1200.

1201.

1202.

1203.

1204.

1205.

1206.

1207.

1208.

1209.

1210.

1211.

1212.

1213.

1214.

1215.

1216.

1217.

1218.

1219.

1220.

1221.

1222.

1223.

1224.

1225.

1226.

1227.

1228.

1229.

1230.

1231.

1232.

1233.

1234.

1235.

1236.

1237.

1238.

1239.

1240.

1241.

1242.

1243.

1244.

1245.

1246.

1247.

1248.

1249.

1250.

1251.

1252.

1253.

1254.

1255.

1256.

1257.

1258.

1259.

1260.

1261.

1262.

1263.

1264.

1265.

1266.

1267.

Barbiturates

In another embodiment, compounds of the present invention arerepresented by formula XXXIII-XXXVII as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X, X₁, X₂, R₁₀₀, R₁₀₁, and R₁ are as defined above;X₁₀ is —S or —O.

In a preferred embodiment a compound from Table XXXIII-XXXVII isprovided. A more preferred embodiment is a compound of tableXXXIII-XXXVII wherein R₁ is selected from tables 1-4.

TABLE XXXIII-XXXIV 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

Pyridone Pyrimidone and Pyrimidione Prodrugs

In another embodiment, compounds of the present invention arerepresented by formula XXXVIII or XXXIX as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein X, R₁, R₃, R₄, m and q are as defined above;X₁₁ is —N— or —C(R₁₀)—;X₁₂ is —C(O)—, —C(S)—, —C(R₁₀)(R₁₁)— or —C(R₁₀)(OR₁₁)—; and,X₁₃ is —O, —S, —N(R₁₀)(R₁₁), —OR₁₀.

A preferred embodiment is a compound selected from table XXXVIII-XXXIX.A more preferred embodiment is a compound from table XXXVIII-XXXVIXwherein R₁ is selected from tables 1-4.

TABLE XXXVIII 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

Prodrugs of Benzamide Pharmacophores

In another embodiment, compounds of the present invention arerepresented by formula XL or XLI as illustrated below, and the geometricisomers, enantiomers, diastereomers, racemates, pharmaceuticallyacceptable salts and solvates thereof:

wherein R₁, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ are as defined above.

TABLE XL-XLI

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42Prodrugs of Imide Pharmacophores

In another embodiment, compounds of the present invention arerepresented by formula XLII, XLIII or XLIV as illustrated below, and thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁ R₁₀₀, R₁₀₁, X, X₁ and X₂ are as defined above; alternativelyR₁₀₀ and R₁₀₁ together with the atoms to which they are attached form anoptionally substituted 3, 4, 5, 6, or 7 membered ring.

A preferred embodiment is a compound selected from table XLII-XLIV. Amore preferred embodiment is a compound from table XLII-XLIV wherein R₁is selected from tables 1-4.

TABLE XLII-XLIV XLII-

1

2

3

4

5

6

7

8

9

10

11

12

13

14 XLIII-

1

2

3

4

6

6

7

8

9

10

11

12

13

14

15

16 XLIV-

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

In another embodiment, compounds of the present invention having theformula IV-VII is selected from table IV-V.

TABLE IV-VII

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

53

54Prodrugs of Sulfonamide Pharmacophores

In another embodiment, compounds of the present invention arerepresented by formula III as illustrated below, or its geometricisomers, enantiomers, diastereomers, racemates, pharmaceuticallyacceptable salts and solvates thereof:

A preferred embodiment is a compound selected from table III. A morepreferred embodiment is a compound from table III wherein R₁ is selectedfrom tables 1-4.

TABLE III

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

59

60

61

62

63

64

65

66

67

68

69

70

71

Chlorothiazide and hydrochlorothiazide compounds of formula III and inparticular table III are useful for the treatment of hypertension,congestive heart failure, osteoporosis, symptomatic edema peripheraledema, kidney stones, diabetes, nephrogenic diabetes insipidus,hypercalcaemia, Dent's disease and Meniere's disease. Compounds offormula III and table III provide sustained release of parent drugs bycleavage of the labile R₁ moiety. Compounds of formula III, for exampleIII-63 to III-71 are useful as prodrugs for the treatment of diabetes.

In another aspect of the invention a general method to convert compoundsof Formula XLV with secondary amides to substituted tertiary amides isprovided (Scheme 1).

In addition to the reaction of aldehyde or ketone to compounds offormula XLV, other process for converting secondary lactam groups can beused. For example, alkylation followed by addition of sodium in inertsolvents, or addition of potassium hydroxide or sodium hydroxidefollowed by alkyl halide addition can be used. Microwave based syntheticprocedures can also be used to convert secondary lactams to substitutedtertiary lactam compounds of the instant application. (For a generalreview see March J. Advanced Organic Chemistry, Wiley, 1992; Inoue etal., Bull. Chem. Soc. Jpn., 58, 2721-2722, 1985; Mijin et al., J. Serb.Chem. Soc., 73(10) 945-950, 2008; Bogdal et al. Molecules, 1999, 4,333-337; U.S. Pat. No. 5,041,659).

The invention further relates the sustained delivery of a compound offormula XLV by the administration of a compound of formula I-III. Uponadministration of a compound of formula I-III, the labile R₁ moiety maybe cleaved off enzymatically, chemically or through first phasemetabolism giving a compound of formula XLV. Without being bound to anytheory, it is postulated that for some of the compounds of formulaI-III, the release of a compound of formula XLV upon cleavage of the R₁moiety results in a therapeutically active agent. For example, suchactive ingredient can be aripiprazole, ziprasidone or bifeprunox. In oneembodiment, the sustained release comprises a therapeutically effectiveamount of a compound of formula XLV in the blood stream of the patientfor a period of at least about 8, preferably at least about 12, morepreferably at least about 24 and even more preferably at least about 36hours after administration of a compound of formula I-III. In oneembodiment, the compound of formula XLV is present in the blood streamof the patient for a period selected from: at least 48 hours, at least 4days, at least one week, and at least one month. In one embodiment, acompound of formula I—III is administered by injection.

Compounds of formula IX, X, XI, XII, XIII, XIV, XXXIII, XXXIV, XXXV,XXXVI, and XXXVII are useful for the treatment of neurological andpsychological disorders. Neurological and psychiatric disorders include,but are not limited to, disorders such as cerebral deficit subsequent tocardiac bypass surgery and grafting, stroke, cerebral ischemia, spinalcord trauma, head trauma, perinatal hypoxia, cardiac arrest,hypoglycemic neuronal damage, dementia (including AIDS-induceddementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateralsclerosis, ocular damage, retinopathy, cognitive disorders, idiopathicand drug-induced Parkinson's disease, muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions, cerebral deficits secondary to prolonged statusepilepticus, migraine (including migraine headache), urinaryincontinence, substance tolerance, substance withdrawal (including,substances such as opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,schizophrenia, anxiety (including generalized anxiety disorder, panicdisorder, social phobia, obsessive compulsive disorder, andpost-traumatic stress disorder (PTSD)), mood disorders (includingdepression, mania, bipolar disorders), circadian rhythm disorders(including jet lag and shift work), trigeminal neuralgia, hearing loss,tinnitus, macular degeneration of the eye, emesis, brain edema, pain(including acute and chronic pain states, severe pain, intractable pain,neuropathic pain, inflammatory pain, and post-traumatic pain), tardivedyskinesia, sleep disorders (including narcolepsy), attentiondeficit/hyperactivity disorder, eating disorders and conduct disorder.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aliphatic group” or “aliphatic” refers to a non-aromaticmoiety that may be saturated (e.g. single bond) or contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic, contain carbon,hydrogen or, optionally, one or more heteroatoms and may be substitutedor unsubstituted. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groups mayinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, and substituted or unsubstituted cycloalkyl groupsas described herein.

The term “acyl” refers to a carbonyl substituted with hydrogen, alkyl,partially saturated or fully saturated cycloalkyl, partially saturatedor fully saturated heterocycle, aryl, or heteroaryl. For example, acylincludes groups such as (C₁-C₆) alkanoyl (e.g., formyl, acetyl,propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively.

The term “alkyl” is intended to include both branched and straightchain, substituted or unsubstituted saturated aliphatic hydrocarbonradicals/groups having the specified number of carbons. Preferred alkylgroups comprise about 1 to about 24 carbon atoms (“C₁-C₂₄”) preferablyabout 7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about24 carbon atoms (“C₈-C₂₄”), preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkyl groups comprise at about 1 to about 8carbon atoms (“C₁-C₈”) such as about 1 to about 6 carbon atoms(“C₁-C₆”), or such as about 1 to about 3 carbon atoms (“C₁-C₃”).Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl,neopentyl and n-hexyl radicals.

The term “alkenyl” refers to linear or branched radicals having at leastone carbon-carbon double bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkenyl radicals are “lower alkenyl”radicals having two to about ten carbon atoms (“C₂-C₁₀”) such asethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Preferred loweralkenyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”). The terms“alkenyl”, and “lower alkenyl”, embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkynyl” refers to linear or branched radicals having at leastone carbon-carbon triple bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkynyl radicals are “lower alkynyl”radicals having two to about ten carbon atoms such as propargyl,1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl. Preferredlower alkynyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”).

The term “cycloalkyl” refers to saturated carbocyclic radicals havingthree to about twelve carbon atoms (“C₃-C₁₂”). The term “cycloalkyl”embraces saturated carbocyclic radicals having three to about twelvecarbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “cycloalkenyl” refers to partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkylene,” as used herein, refers to a divalent group derivedfrom a straight chain or branched saturated hydrocarbon chain having thespecified number of carbons atoms. Examples of alkylene groups include,but are not limited to, ethylene, propylene, butylene,3-methyl-pentylene, and 5-ethyl-hexylene.

The term “alkenylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbondouble bond. Alkenylene groups include, but are not limited to, forexample, ethenylene, 2-propenylene, 2-butenylene,1-methyl-2-buten-1-ylene, and the like.

The term “alkynylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbontriple bond. Representative alkynylene groups include, but are notlimited to, for example, propynylene, 1-butynylene,2-methyl-3-hexynylene, and the like.

The term “alkoxy” refers to linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty-four carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” refers to alkyl radicals having one or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”refer to saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a pentavalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” refers to unsaturated aromatic heterocyclylradicals. Examples of heteroaryl radicals include unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” refers to heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocyclo radical.

The term “alkylthio” refers to radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty-four carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred alkylthio radicals have alkyl radicalswhich are “lower alkylthio” radicals having one to about ten carbonatoms. Most preferred are alkylthio radicals having lower alkyl radicalsof one to about eight carbon atoms. Examples of such lower alkylthioradicals include methylthio, ethylthio, propylthio, butylthio andhexylthio.

The terms “aralkyl” or “arylalkyl” refer to aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” refers to aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” refer to aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” refers to alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty-four carbon atoms or, preferably, one to abouttwelve carbon atoms. More preferred aminoalkyl radicals are “loweraminoalkyl” that have alkyl radicals having one to about ten carbonatoms. Most preferred are aminoalkyl radicals having lower alkylradicals having one to eight carbon atoms. Examples of such radicalsinclude aminomethyl, aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkyl sulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “halogen” or “halo” as used herein, refers to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The terms “compound” “drug”, and “prodrug” as used herein all includepharmaceutically acceptable salts, co-crystals, solvates, hydrates,polymorphs, enantiomers, diastereoisomers, racemates and the like of thecompounds, drugs and prodrugs having the formulas as set forth herein.

Substituents indicated as attached through variable points ofattachments can be attached to any available position on the ringstructure.

As used herein, the term “effective amount of the subject compounds,”with respect to the subject method of treatment, refers to an amount ofthe subject compound which, when delivered as part of desired doseregimen, brings about management of the disease or disorder toclinically acceptable standards.

“Treatment” or “treating” refers to an approach for obtaining beneficialor desired clinical results in a patient. For purposes of thisinvention, beneficial or desired clinical results include, but are notlimited to, one or more of the following: alleviation of symptoms,diminishment of extent of a disease, stabilization (i.e., not worsening)of a state of disease, preventing spread (i.e., metastasis) of disease,preventing occurrence or recurrence of disease, delay or slowing ofdisease progression, amelioration of the disease state, and remission(whether partial or total).

The term “labile” as used herein refers to the capacity of the prodrugof the invention to undergo enzymatic and/or chemical cleavage in vivothereby forming the parent drug. As used herein the term “prodrug” meansa compounds as disclosed herein which is a labile derivative compound ofa heteroaromatic NH-containing parent drug which when administered to apatient in vivo becomes cleaved by chemical and/or enzymatic hydrolysisthereby forming the parent drug such that a sufficient amount of thecompound intended to be delivered to the patient is available for itsintended therapeutic use in a sustained release manner.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid, gel or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;cyclodextrins such as alpha-(α), beta-(β) and gamma-(γ) cyclodextrins;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. In a preferredembodiment, administration is parenteral administration by injection.

The pharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesuspension or emulsion, such as INTRALIPID®, LIPOSYN® or OMEGAVEN®, orsolution, in a nontoxic parenterally acceptable diluent or solvent, forexample, as a solution in 1,3-butanediol. INTRALIPID® is an intravenousfat emulsion containing 10-30% soybean oil, 1-10% egg yolkphospholipids, 1-10% glycerin and water. LIPOSYN® is also an intravenousfat emulsion containing 2-15% safflower oil, 2-15% soybean oil, 0.5-5%egg phosphatides 1-10% glycerin and water. Omegaven® is an emulsion forinfusion containing about 5-25% fish oil, 0.5-10% egg phosphatides,1-10% glycerin and water. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution, USP and isotonicsodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are used inthe preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Additional sustained release in accordance with the invention may beaccomplished by the use of a liquid suspension of crystalline oramorphous material with poor water solubility. The rate of absorption ofthe drug then depends upon its rate of dissolution, which, in turn, maydepend upon crystal size and crystalline form. Alternatively, delayedabsorption of a parenterally administered drug form is accomplished bydissolving or suspending the drug in an oil vehicle. Injectable depotforms are made by forming microencapsule matrices of the drug inbiodegradable polymers such as polylactide-polyglycolide. Depending uponthe ratio of drug to polymer and the nature of the particular polymeremployed, the rate of drug release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping the drugin liposomes or microemulsions that are compatible with body tissues.

In one preferred embodiment, the formulation provides a sustainedrelease delivery system that is capable of minimizing the exposure ofthe prodrug to water. This can be accomplished by formulating theprodrug with a sustained release delivery system that is a polymericmatrix capable of minimizing the diffusion of water into the matrix.Suitable polymers comprising the matrix include polylactide (PLA)polymers and the lactide/glycolide (PLGA) co-polymers.

Alternatively, the sustained release delivery system may comprisepoly-anionic molecules or resins that are suitable for injection or oraldelivery. Suitable polyanionic molecules include cyclodextrins andpolysulfonates formulated to form a poorly soluble mass that minimizesexposure of the prodrug to water and from which the prodrug slowlyleaves.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

By a “therapeutically effective amount” of a prodrug compound of theinvention is meant an amount of the compound which confers a therapeuticeffect on the treated subject, at a reasonable benefit/risk ratioapplicable to any medical treatment. The therapeutic effect may beobjective (i.e., measurable by some test or marker) or subjective (i.e.,subject gives an indication of or feels an effect).

In accordance with the invention, the therapeutically effective amountof a prodrug of the invention is typically based on the targettherapeutic amount of the parent drug. Information regarding dosing andfrequency of dosing is readily available for many parent drugs fromwhich the prodrugs of the invention are derived and the targettherapeutic amount can be calculated for each prodrug of the invention.In accordance with the invention, the same dose of a prodrug of theinvention provides a longer duration of therapeutic effect as comparedto the parent drug. Thus if a single dose of the parent drug provides 12hours of therapeutic effectiveness, a prodrug of that same parent drugin accordance with the invention that provides therapeutic effectivenessfor greater than 12 hours will be considered to achieve a “sustainedrelease”.

The precise dose of a prodrug of the invention depends upon severalfactors including the nature and dose of the parent drug and thechemical characteristics of the prodrug moiety linked to the parentdrug. Ultimately, the effective dose and dose frequency of a prodrug ofthe invention will be decided by the attending physician within thescope of sound medical judgment. The specific therapeutically effectivedose level and dose frequency for any particular patient will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcontemporaneously with the specific compound employed; and like factorswell known in the medical arts.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims. General methodology forthe preparation of lactam compounds can be found in the followingpublications: U.S. Pat. No. 7,160,888; U.S. Pat. No. 5,462,934; U.S.Pat. No. 4,914,094; U.S. Pat. No. 4,234,584; U.S. Pat. No. 4,514,401;U.S. Pat. No. 5,462,934; U.S. Pat. No. 4,468,402; WO 2006/090273 A2; WO2008/150848 A1; WO 2006/112464 A1; WO 2008/132600 A1.

Preparation of7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one(Example 1: Compound A1)

A mixture of Aripiprazole (20 g, 45 mmol), triethylamine (1 mL, 7.1mmol), formaldehyde (37% aqueous solution, 70 mL) and dimethylformamide(200 mL) was heated to 80° C. for 20 h. The reaction mixture was cooled,diluted with ethyl acetate (400 mL) and washed with water/brine (1:1,3×500 mL). The organic phase was dried over MgSO₄, filtered andevaporated to dryness under vacuum to give hemi-aminal A1 as a whitesolid (18.6 g, containing 25% Aripiprazole, 65% yield based on A1).

¹H NMR (CDCl₃, 300 MHz) complex mixture of signals due to contaminationwith Aripiprazole, main signal δ 5.34 (s, 2H, OHCH ₂N); m/z (M⁺H) 478and 480.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylbenzylcarbamate (Example 2: Compound 28)

To a solution of hemi-aminal, A1, from Example 1 (4 g, 8.4 mmol),4-dimethylaminopyridine (0.15 g, 1.3 mmol) and triethylamine (1.1 mL,7.5 mmol) in dichloromethane (30 mL) was added benzylisocyanate (1.03mL, 8.3 mmol) and the reaction mixture stirred for 24 hours. Thereaction mixture was then heated at 35° C. for 20 hours, cooled andwashed with water/brine (1:1, 50 mL). The organic phase was dried overMgSO₄, filtered and evaporated under vacuum. The residue was furtherpurified by chromatography on silica eluting with ethylacetate/dichloromethane/methanol (1:1:0.1) to give the desired productas an off white foam (530 mg, 14% yield). ¹H NMR (CDCl₃, 300 MHz) δ1.58-1.88 (m, 4H), 2.48 (t, 2H), 2.60-2.72 (m, 6H), 2.85 (m, 2H),300-3.12 (m, 4H), 3.96 (t, 2H), 4.40 (d, 2H), 5.13 (NH), 5.96 (s, 2H),6.58 (dd, 1H), 6.79 (d, 1H), 6.92-6.98 (m, 1H), 7.04 (d, 1H), 7.12-7.16(m, 1H), 7.23-7.35 (m, 6H); m/z (M⁺H) 611.12 and 613.10.

The following compounds were prepared in an analogous fashion to Example2.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylethyl carbonate (Example 3: Compound 79)

The desired product was isolated as a yellow oil (830 mg, 24% yield). ¹HNMR (d₆-DMSO, 300 MHz) δ 1.78 (t, 3H), 1.52-1.61 (m, 2H), 1.63-1.76 (m,2H), 2.31-2.40 (m, 2H), 2.40-2.60 (m, 6H), 2.73-2.80 (m, 2H), 2.91-2.99(m, 4H), 3.96 (t, 3H), 4.11 (q, 2H), 5.87 (s, 2H), 6.60-6.70 (m, 2H),7.07-7.12 (m, 2H), 7.24-7.30 (m, 2H); m/z (M⁺H) 550.48 and 552.40.

butyl(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylcarbonate (Example 4: Compound 80)

The desired product was isolated as a yellow oil (750 mg, 21% yield). ¹HNMR (CDCl₃, 300 MHz) δ 0.92 (t, 3H), 1.33-1.45 (m, 2H), 1.59-1.80 (m,4H), 1.80-1.92 (m, 2H), 2.49 (t, 2H), 2.58-2.75 (m, 6H), 2.85 (t, 2H),3.00-3.13 (m, 4H), 3.98 (t, 2H), 4.18 (t, 2H), 5.92 (s, 2H), 6.58 (dd,1H), 6.67 (d, 1H), 6.92-6.99 (m, 1H), 7.03 (dd, 1H), 7.10-7.20 (m, 2H);m/z (M⁺H) 578.10 and 580.08.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylhexyl carbonate (Example 5: Compound 81)

The desired product was isolated as a yellow oil (1.77 g, 62% yield). ¹HNMR (d₆-DMSO, 300 MHz) δ 0.80 (t, 3H), 1.15-1.30 (m, 6H), 1.50-1.60 (m,4H), 1.65-1.73 (m, 2H), 2.35 (t, 2H), 2.41-2.60 (m, 6H), 2.78 (t, 2H),2.88-3.00 (m, 4H), 3.95 (t, 2H), 4.06 (t, 2H), 5.86 (s, 2H), 6.60-6.70(m, 2H), 7.05-7.15 (m, 2H), 7.22-7.28 (m 2H); m/z (M⁺H) 606.15 and608.15.

decyl(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylcarbonate (Example 6: Compound 82)

The desired product was isolated as a yellow oil (1.42 g, 46% yield). ¹HNMR (d₆-DMSO, 300 MHz) δ 0.79 (m, 3H), 1.13-1.30 (m, 14H), 1.48-1.60 (m,4H), 1.65-1.75 (m, 2H), 2.33 (t, 2H), 2.41-2.60 (m, 6H), 2.72-2.80 (m,2H), 2.89-2.98 (m, 4H), 3.95 (t, 2H), 4.05 (t, 2H), 5.86 (s, 2H),6.60-6.70 (m, 2H), 7.05-7.13 (m, 2H), 7.22-7.28 (m, 2H); m/z (M⁺H)662.56 and 664.54.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylhexadecyl carbonate (Example 7: Compound 83)

The desired product was isolated as a yellow oil (1.55 g, 44% yield). ¹HNMR (d₆-DMSO, 300 MHz) δ 0.80 (t, 3H), 1.10-1.29 (m, 26H), 1.49-1.60 (m,4H), 1.65-1.75 (m, 2H), 2.33 (t, 2H), 2.43-2.55 (m, 6H), 2.78 (t, 2H),2.90-2.95 (m, 4H), 3.95 (t, 2H), 4.05 (t, 2H), 5.84 (s, 2H), 6.60-6.68(m, 2H), 7.05-7.12 (m, 2H), 7.24-7.29 (m, 2H); m/z (M-C₁₀H₂₀)⁺ 606.52and 608.54.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylmorpholine-4-carboxylate (Example 8: Compound 49)

The desired product was isolated as a yellow oil (1.52 g, 55% yield). ¹HNMR (d₆-DMSO, 300 MHz) δ 1.50-1.75 (m, 4H), 2.35 (t, 2H), 2.42-2.61 (m,6H), 2.70-2.82 (m, 2H), 2.88-3.00 (m, 4H), 3.26-3.40 (m, 4H), 3.40-3.60(m, 4H), 3.94 (t, 2H), 5.81 (s, 2H), 6.61 (dd, 1H), 6.68 (d, 1H),7.05-7.13 (m, 2H), 7.20-7.30 (m, 2H); m/z (M⁺H) 591.11 and 593.15.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldiethylcarbamate (Example 9: Compound 84)

The desired product was isolated as a yellow oil (0.83 g, 31% yield). ¹HNMR (CDCl₃, 300 MHz) δ 1.00-1.20 (m, 6H), 1.65-1.88 (m, 4H), 2.45-2.52(m, 2H), 2.58-2.83 (m, 6H), 2.82-2.90 (m, 2H), 3.00-3.12 (m, 4H),3.18-3.38 (m, 4H), 3.97 (t, 2H), 5.91 (s, 2H), 6.58 (dd, 1H), 6.77 (d,1H), 6.94-6.98 (m, 1H), 7.06 (d, 1H), 7.15-7.20 (m, 2H); m/z (M⁺H)577.48 and 579.46.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylisopentyl carbonate (Example 10: Compound 85)

To a solution of phosgene (20% in toluene, 54 mL, 110 mmol) intetrahydrofuran (100 mL) was added a solution of 3-methyl-1-butanol (1.7mL, 15.7 mmol) in tetrahydrofuran (50 mL) over 1 hour. After 4 hours thevolatiles were removed under vacuum and the residue added to a solutionof the hemi-aminal A1 (3 g, 4.7 mmol), 4-dimethylaminopyridine (0.3 g,1.9 mmol), pyridine (10 mL) and triethylamine (1.3 mL, 9.4 mmol) indichloromethane (30 mL). After being stirred for 72 hours, the reactionmixture was diluted with ethyl acetate (100 mL) and washed with 5%aqueous NaHCO₃/brine (1:1, 100 mL). The organic phase was dried overMgSO₄, filtered and evaporated under vacuum. The residue was furtherpurified by chromatography on silica eluting with ethylacetate/dichloromethane/methanol (1:1:0.1) to give the desired productas a yellow oil (1.54 g, 55% yield). ¹H NMR (CDCl₃, 300 MHz) δ 1.90-1.95(m, 6H), 1.50-1.60 (m, 4H), 1.65-1.79 (m, 2H), 1.79-1.89 (m, 2H), 2.50(t, 2H), 2.60-2.72 (m, 6H), 2.82-2.90 (m, 2H), 3.02-3.11 (m, 4H), 3.98(t, 2H), 4.21 (t, 2H), 5.92 (s, 2H), 6.56 (dd, 1H), 6.67 (d, 1H),6.95-7.00 (m, 1H), 7.05 (d, 1H), 7.13-7.19 (m, 2H); m/z (M⁺H) 592.48 and594.46.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylacetate (Example 11: Compound 1)

A solution of Compound-A1 from Example-1, (50.63 g, 0.105 mol) inanhydrous tetrahydrofuran (THF, 80 mL) was treated with acetic anhydride(15.3 mL, 0.16 mol) and heated for 2.0 hours at 60° C. (oil-bath). Tothe above solution, triethylamine (2.0 mL, 0.014 mol) was added andstirred for 16 hours at 60° C. The solvent was removed using a rotatorevaporator. To the resulting crude mixture, ethyl acetate (150 mL) andheptane (50 mL) was added. The solution was washed with NaHCO₃ (5%aqueous solution, 250 mL). After separation of the two layers, pH of theaqueous layer was adjusted to above 7. The aqueous layer was furtherextracted using the organic mixture. The organic layer was separated andwashed with 5% NaHCO₃ solution, followed by deionized water, and brine.The solution was dried using anhydrous MgSO₄, filtered and evaporatedunder vacuum. The resulting product was purified using silica gel columnchromatography using ethanol:ethyl acetate (5:95) as the eluent.Fractions containing the desired product were combined and d-tartaricacid (12.5 g dissolved in 60:5 ethanol:water) was added, resulting inthe precipitation of the desired product (48.78 g, 89% yield). ¹H NMR(CDCl₃, 300 MHz) δ 1.73 (m, 2H), 1.84 (m, 2H), 2.12 (s, 3H), 2.50 (t,2H), 2.68 (m, 6H), 2.87 (dd, 2H), 3.08 (m, 4H), 3.98 (t, 2H), 5.91 (s,2H), 6.59 (m, 2H), 6.96 (dd, 1H), 7.08 (dd, 1H), 7.15 (m, 2H).

The following compounds were prepared in an analogous fashion to Example11.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate (Example 12: Compound 7)

The desired product was isolated as a crystalline solid (0.3 g, 21%yield). The molecular weight was confirmed by mass spectrometeranalysis. FIG. 2-6 shows the PXRD, IR, Raman, TGA spectrum of thedesired product. ¹H NMR (CDCl₃, 300 MHz) δ 0.87 (t, 3H), 1.24 (m, 16H),1.62 (m, 2H), 1.83 (m, 2H), 1.86 (m, 2H), 2.36 (t, 2H), 2.49 (t, 2H),2.68 (m, 6H), 2.86 (dd, 2H), 3.08 (m, 4H), 3.97 (t, 2H), 5.91 (s, 2H),6.59 (m, 2H), 6.96 (dd, 1H), 7.07 (dd, 1H), 7.14 (m, 2H). See Figuresx-y for further characterization (PXRD, IR, Raman, TGA and DSC spectra)of Compound 7.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylpalmitate (Example 13: Compound 10)

The desired product was isolated as a crystalline solid (4.2 g, 70%yield). The molecular weight (716.6) was confirmed by mass spectrometeranalysis. ¹H NMR (CDCl₃, 300 MHz) δ 0.88 (t, 3H), 1.25 (m, 24H), 1.64(m, 2H), 1.72 (m, 2H), 1.84 (m, 2H), 2.36 (t, 2H), 2.49 (t, 2H), 2.68(m, 6H), 2.86 (dd, 2H), 3.08 (m, 4H), 3.97 (t, 2H), 5.92 (br s, 2H),6.59 (dd, 1H), 6.60 (s, 1H), 6.96 (dd, 1H), 7.07 (d, 1H), 7.14 (m, 2H).

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldecanoate (Example 14: Compound 6)

The chloromethyl ester above is dried over 4 Å molecular sieves. Asolution of aripiprazole (45 grams, 0.1 mol) in 1,4-dioxane (800 mL) wassonicated to dissolve the aripiprazole completely, and then treated withNaH (38 g, 0.95 mol, 60% dispersion) in one portion. After stirring thisreaction mixture for 15 minutes at room temperature, the reactionmixture was treated dropwise with chloromethyl ester (0.3 mol.) and acatalytic amount of sodium iodide (0.05 mol). The resultant cloudymixture was heated to 90° C. for 2 hours, cooled to ambient temperatureand poured into water. The product was extracted with ethyl acetate, andthe combined ethyl acetate layers washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. Columnchromatography over silica gel provided the desired product (12.5 gram,70% yield). ¹H NMR (CDCl₃, 300 MHz) δ 0.87 (t, 3H), 1.20 (m, 12H), 1.63(m, 2H), 1.70 (m, 2H), 1.83 (m, 2H), 2.35 (t, 2H), 2.50 (t, 2H), 2.68(m, 6H), 2.86 (t, 2H), 3.08 (m, 4H), 3.97 (t, 2H), 5.92 (s, 2H), 6.58(dd, 1H), 6.61 (d, 1H), 6.94 (dd, 1H), 7.06 (d, 1H), 7.14-7.17 (m, 2H);m/z (M⁺H) 632.88.

The following compounds (Examples 15-29) were prepared in an analogousfashion to Example 2:

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylbenzoate (Example 15: Compound 31)

The desired product was isolated as a yellow oil.

¹H NMR (CDCl₃, 300 MHz) δ 1.60-1.85 (m, 4H), 2.45 (t, 2H), 2.55-2.70 (m,4H), 2.70-2.78 (m, 2H), 2.85-2.92 (m, 2H), 3.00-3.10 (m, 4H), 3.94 (t,2H), 6.16 (s, 2H), 6.60 (d, 1H), 6.72 (dd, 1H), 6.90-6.95 (m, 1H),7.05-7.18 (m, 2H), 7.35-7.42 (m, 2H), 7.52-7.60 (m, 1H), 8.00-8.08 (m,2H). m/z (M⁺H) 582.3.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylbutyrate (Example 16: Compound 2)

The desired product was isolated by chromatography on silica elutingwith ethyl acetate/dichloromethane/methanol (1:1:0.1) to give a yellowoil (2.0 g, 87% yield). ¹H NMR (CDCl₃, 300 MHz) δ 0.94 (t, 3H),1.60-1.90 (m, 6H), 2.34 (t, 2H), 2.51 (t, 2H), 2.61-2.73 (m, 6H),2.82-2.90 (m, 2H), 3.02-3.12 (m, 4H), 3.96 (t, 2H), 5.91 (s, 1H),6.55-6.61 (m, 2H), 6.93-6.98 (m, 1H), 7.05 (d, 1H), 7.11-7.18 (m, 2H).m/z (M⁺H) 548.2 and 550.2.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylhexanoate (Example 17: Compound 4)

The desired product was isolated as a yellow solid (3.69 g, 87% yield).¹H NMR (CDCl₃, 300 MHz) δ 0.78 (t, 3H), 1.11-1.28 (m, 4H), 1.40-1.78 (m,6H), 2.20-2.40 (m, 4H), 2.40-2.60 (m, 6H), 2.73-2.81 (m, 2H), 2.85-3.00(m, 4H), 3.88-4.00 (m, 2H), 5.75-5.83 (m, 2H), 6.55-6.62 (m, 2H),7.03-7.12 (m, 2H), 7.20-7.26 (m, 2H). m/z (M⁺H) 576.4 and 578.4.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyltetradecanoate (Example 18: Compound 8)

The desired product was isolated as a pale yellow solid (5.3 g, 74%yield). ¹H NMR (CDCl₃, 300 MHz) δ 0.87 (t, 3H), 1.07-1.37 (m, 22H),1.55-1.70 (m, 2H), 1.70-1.90 (m, 4H), 2.34 (t, 2H), 2.53 (t, 2H),2.65-2.78 (m, 6H), 2.82-2.90 (m, 2H), 3.02-3.12 (m, 4H), 3.96 (t, 2H),5.91 (s, 2H), 6.55-6.62 (m, 2H), 6.92-6.98 (m, 1H), 7.05 (d, 1H),7.11-7.18 (m, 2H). m/z (M⁺H) 688.4 and 690.4.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyloctanoate (Example 19: Compound 5)

The desired product was isolated as a yellow oil (2.2 g, 87% yield). ¹HNMR (CDCl₃, 300 MHz) δ 0.82 (t, 3H), 1.15-1.35 (m, 10H, 1.55-1.87 (m,6H), 2.34 (t, 2H), 2.53 (t, 2H), 2.65-2.73 (m, 4H), 2.85 (dd, 2H),3.01-3.11 (m, 4H), 3.95 (t, 2H), 5.85-5.92 (m, 2H), 2.53-2.60 (m, 2H),6.91-6.97 (m, 1H), 7.05 (d, 1H), 7.10-7.16 (m, 2H). m/z (M⁺H) 604.3 and606.3.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylisopropyl carbonate (Example 20: Compound 48)

The desired product was isolated as an orange oil (2.4 g, 68% yield). ¹HNMR (CDCl₃, 300 MHz) δ 1.31 (d, 6H), 1.62-1.77 (m, 2H), 1.77-1.89 (m,2H), 2.48 (t, 2H), 2.60-2.71 (m, 6H), 2.81-2.90 (m, 2H), 3.01-3.11 (m,4H), 3.98 (t, 2H), 4.89-4.97 (m, 1H), 5.92 (s, 2H), 6.57 (d, 1H), 6.68(d, 1H), 6.91-7.00 (m, 1H), 7.05 (dd, 1H), 7.11-7.18 (m, 2H). m/z (M⁺H)564.3 and 566.3.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylmethylcarbamate (Example 21: Compound 47)

The desired product was isolated as a yellow solid (1.3 g, 52% yield).¹H NMR (CDCl₃, 300 MHz) δ 1.68-1.88 (m, 4H), 2.49 (dd, 2H), 2.60-2.73(m, 6H), 2.80-2.90 (m, 5H), 3.02-3.12 (m, 4H), 3.95-4.02 (m, 2H), 5.90(s, 2H), 6.57 (d, 1H), 6.77 (d, 1H), 6.93-6.70 (m, 1H), 7.05 (d, 1H),7.10-7.19 (m, 2H). m/z (M⁺H) 535.5 and 537.5.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldecylcarbamate (Example 22: Compound 46)

The desired product was isolated as a yellow solid (0.50 g, 14% yield).¹H NMR (CDCl₃, 300 MHz) δ 0.86 (t, 3H), 1.18-1.35 (m, 16H), 1.42-1.53(m, 2H), 1.67-1.79 (m, 2H), 1.79-1.87 (m, 2H), 2.48 (t, 2H), 2.58-2.72(m, 4H), 2.80-2.90 (m, 2H), 3.01-3.12 (m, 4H), 3.15-3.22 (m, 2H), 3.98(t, 2H), 4.78 (NH), 5.90 (s, 2H), 6.58 (d, 1H), 6.78 (d, 1H), 6.93-7.00(m, 1H), 7.04 (d, 1H), 7.10-7.16 (m, 2H). m/z (M⁺H) 661.6 and 663.6.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylisobutyrate (Example 23: Compound 32)

¹H NMR (CDCl₃, 300 MHz) δ 1.18 (d, 6H), 1.68-1.88 (m, 4H), 2.45-2.73 (m,9H), 2.87 (dd, 2H), 3.03-3.12 (m, 2H), 3.95 (t, 2H), 5.91 (s, 2H),6.55-6.60 (m, 2H), 6.93-6.97 (m, 1H), 7.04-7.09 (m, 1H), 7.12-7.19 (m,2H). m/z (M⁺H) 548.15.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylcyclopentanecarboxylate (Example 24: Compound 33)

¹H NMR (CDCl₃, 300 MHz) δ 1.47-1.93 (m, 13H), 2.50-2.60 (m, 2H),2.60-2.90 (m, 8H), 3.02-3.15 (m, 4H), 3.95 (t, 2H), 5.89 (s, 2H),6.50-6.60 (m, 2H), 6.90-6.95 (m, 1H), 7.02-7.07 (m, 1H), 7.10-7.19 (m,2H). m/z (M⁺H) 574.15.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylcyclobutanecarboxylate (Example 25: Compound 34)

¹H NMR (CDCl₃, 300 MHz) δ 1.82-1.91 (m, 3H), 1.22-1.30 (m, 2H),1.75-2.05 (m, 6H), 2.05-2.40 (m, 6H), 2.68-2.73 (m, 2H), 2.84-2.90 (m,2H), 3.06-3.22 (m, 4H), 3.96 (t, 2H), 5.91 (s, 2H), 6.55-6.59 (m, 2H),6.97 (dd, 1H), 7.07 (d, 1H), 7.12-7.18 (m, 2H). m/z (M⁺H) 560.19.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylcyclohexanecarboxylate (Example 26: Compound 35)

¹H NMR (CDCl₃, 300 MHz) δ 1.15-1.35 (m, 3H), 1.35-1.55 (m, 2H),1.55-1.95 (m, 10H), 2.21-2.40 (m, 1H), 2.52-2.60 (m, 1H), 2.62-3.00 (m,8H), 3.02-3.12 (m, 4H), 3.95 (t, 2H), 5.89 (s, 2H), 6.50-6.60 (m, 2H),6.93-6.97 (m, 1H), 7.02-7.06 (m, 1H), 7.10-7.15 (m, 2H). m/z (M⁺H)588.24.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl2-(2-methoxyethoxy)acetate (Example 27: Compound 40)

¹H NMR (CDCl₃, 300 MHz) δ 1.56-1.90 (m, 6H), 2.43-2.55 (m, 2H),2.55-2.80 (m, 4H), 2.81-2.90 (m, 2H), 3.37 (s, 3H), 3.55-3.61 (m, 2H),3.72-3.79 (m, 2H), 4.20 (s, 2H), 5.97 (s, 2H), 6.55-6.59 (m, 2H),6.91-6.98 (m, 1H), 7.09 (d, 1H), 7.11-7.15 (m, 2H). m/z (M⁺H) 594.17.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl2-(2-(2-methoxyethoxy)ethoxy)acetate (Example 28: Compound 41)

¹H NMR (CDCl₃, 300 MHz) δ 1.65-1.93 (m, 6H), 2.49-2.60 (m, 2H),2.61-2.77 (m, 4H), 2.81-2.90 (m, 2H), 3.02-3.20 (m, 4H), 3.36 (s, 3H),3.51-3.57 (m, 2H), 3.60-3.70 (m, 4H), 3.72-3.78 (m, 2H), 3.92-3.99 (m,2H), 4.20 (s, 2H), 5.97 (s, 2H), 6.55-6.59 (m, 2H), 6.95-6.99 (m, 1H),7.05-7.09 (m, 1H), 7.11-7.18 (m, 2H). m/z (M⁺H) 638.30.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylpivalate (Example 29: Compound 42)

¹H NMR (CDCl₃, 300 MHz) δ 1.21 (s, 9H), 1.65-1.88 (m, 4H), 2.45-2.55 (m,2H), 2.60-2.73 (m, 6H), 2.82-2.91 (m, 2H), 3.02-3.13 (m, 4H), 3.95 (t,2H), 5.89 (s, 2H), 6.54-6.60 (m, 2H), 6.92-6.99 (m, 1H), 7.06 (d, 1H),7.13-7.17 (m, 2H); m/z (M⁺H) 562.39.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl2-hydroxyethylcarbamate (Example 30: Compound 36)

2-(((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methoxy)carbonylamino)ethylmethacrylate (2.0 g) was synthesized in a similar manner to Example 2.This was reacted with 16% NH₃/MeOH at room temperature for 18 hours andthen concentrated at 40° C. The residue was purified by silicachromatography eluting with 1:1:0.1 to 1:1:0.2 DCM/EtOAc/MeOH. Theresulting yellow oil was re-crystallised from EtOAc/heptane to give thetitle compound as a white solid (1.2 g, 67%).

¹H NMR (CDCl₃, 300 MHz) δ 1.60-1.88 (m, 4H), 2.40-2.50 (m, 2H),2.50-2.75 (m, 6H), 2.75-2.89 (m, 2H), 2.95-3.15 (m, 4H), 3.20-3.40 (m,2H), 2.58-3.78 (m, 2H), 3.89-4.05 (m, 2H), 5.30-5.45 (m, NH), 5.91 (s,2H), 6.55 (dd, 1H), 6.73 (d, 1H), 6.91-6.96 (m, 1H), 6.98-7.03 (m, 1H),7.04-7.18 (m, 2H). m/z (M⁺H) 565.16.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylbis(2-hydroxyethyl)carbamate (Example 31: Compound 37)

To a solution of hemiaminal A1 (2 g, 0.0042 mol) in dichloromethane (30mL) at room temperature was added pyridine (0.68 mL), followed byp-nitrophenylchloroformate (1.27 g, 0.0063 mol). After 90 minutesdiethanolamine (3.5 g, 0.0334 mol) and triethylamine (1.2 mL, 0.084 mol)were added. After 3 h the reaction was diluted with dichloromethane andwashed with sat. NaHCO₃, dried over MgSO₄ and evaporated. The residuewas purified on silica eluting with 1:1:0.1 to 1:1:0.2 DCM/EtOAc/MeOH togive the title compound as a colourless gum (0.83 g, 33%).

¹H NMR (CDCl₃, 300 MHz) δ 1.70-1.82 (m, 4H), 2.42-2.52 (m, 2H),2.59-2.79 (m, 6H), 2.80-2.90 (m, 2H), 3.00-3.12 (m, 4H), 3.40-3.48 (m,2H), 3.50-3.58 (m, 2H), 3.61-3.70 (m, 2H), 3.85-3.90 (m, 2H), 3.99-4.06(m, 2H), 5.90 (m, 2H), 6.57 (d, 1H), 6.70 (dd, 1H), 6.92-6.98 (m, 1H),7.07 (d, 1H), 7.10-7.20 (m, 2H). m/z (M⁺H) 609.21.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl4-methylpiperazine-1-carboxylate (Example 32: Compound 38)

Compound 141 was synthesized in a similar manner to Example 28.

¹H NMR (CDCl₃, 300 MHz) δ 1.68-1.88 (m, 4H), 2.25-2.42 (m, 7H),2.45-2.55 (m, 2H), 2.61-2.76 (m, 6H), 2.85 (dd, 2H), 3.02-3.16 (m, 4H),3.40-3.60 (m, 4H), 3.97 (t, 2H), 5.92 (s, 2H), 6.59 (d, 1H), 6.74 (d,1H), 6.92-6.98 (m, 1H), 7.02-7.07 (m, 1H), 7.10-7.16 (m, 2H). m/z (M⁺H)604.24.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl1,4′-bipiperidine-1′-carboxylate (Example 33: Compound 39)

Compound 142 was synthesized in a similar manner to Example 28.

¹H NMR (CDCl₃, 300 MHz) δ 1.26-2.06 (m, 14H), 2.31-2.91 (m, 17H),2.95-3.18 (m, 4H), 3.97 (t, 2H), 4.0-4.37 (m, 2H), 5.91 (s, 2H), 6.58(dd, 1H), 6.74 (d, 1H), 6.90-6.99 (m, 1H), 7.05 (d, 1H), 7.11-7.18 (m,2H); m/z (M⁺H) 672.25.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(methoxymethyl)-3,4-dihydroquinolin-2(1H)-one(Example 34: Compound 100)

To a mixture of hemiaminal A1 (2.0 g, 4.2 mmol) in dichloromethane (20mL) was added thionyl chloride (1.5 mL, 12.6 mmol) and stirred for 2 hat room temperature. To the reaction mixture was added methanol (10 mL)and stirred a further 2 h. The reaction poured into NaHCO₃ (aq) andextracted with dichloromethane. The organic phase dried over MgSO₄,evaporated and the residue purified on silica eluting with 1:1:0.1dichloromethane/ethyl acetate/methanol to give the title compound as acream solid (1.3 g, 63%).

¹H NMR (CDCl₃, 300 MHz) δ 1.65-1.83 (m, 4H), 2.47 (t, 2H), 2.58-2.70 (m,6H), 2.82 (dd, 2H), 2.99-3.01 (m, 4H), 3.38 (s, 3H), 3.96 (t, 2H), 5.27(s, 2H), 6.55 (dd, 1H), 6.88 (dd, 1H), 6.91-6.96 (m, 1H), 7.03 (d, 1H),7.08-7.15 (m, 2H). m/z (M⁺H) 492.05.

1-(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)-2-ethoxy-2-oxoethyldecanoate (Example 35: Compound 111)

A mixture of Aripiprazole (2.0 g, 4.5 mmol), ethyl glyoxylate (50% soln.in toluene, 2.7 mL), K₂CO₃ (0.49 g, 3.6 mmol), tetrabutylammoniumbromide (0.57 g, 1.8 mmol) and dichloromethane (20 mL) was heated atreflux for 4 h. The reaction mixture was cooled and quickly washed withwater, dried over MgSO₄ and filtered. The resulting solution was treatedwith pyridine (1.8 mL, 22.2 mmol) and then decanoylchloride (4.6 mL,22.2 mmol). After being stirred for 3 h, methanol (1 mL) was added andstirred a further 10 min. The reaction mixture was washed withsat.NaHCO₃ (aq), dried over MgSO₄ and evaporated. The residue waspurified on silica eluting with 1:1:0.1 dichloromethane/ethylacetate/methanol to give the title compound as a yellow oil (1.2 g,38%).

¹H NMR (CDCl₃, 300 MHz) δ 0.86 (t, 3H), 1.11 (t, 3H), 1.05-1.40 (m,12H), 1.59-1.75 (m, 2H), 1.75-1.98 (m, 4H), 2.40-2.54 (m, 2H), 2.60-3.07(m, 10H), 3.15-3.32 (m, 4H), 3.89-3.99 (m, 2H), 4.09-4.21 (m, 2H), 6.57(dd, 1H), 6.67 (d, 1H), 6.95-7.00 (m, 1H), 7.08 (dd, 1H), 7.12-7.20 (m,2H), 7.27-7.32 (m, 1H). m/z (M⁺H) 704.38.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl4-acetamidobutanoate (Example 36: Compound 44)

To a suspension of hemiaminal A1 (2.6 g, 5.5 mmol) in dichloromethane(30 mL) was added triethylamine (2.3 mL, 16.4 mmol), followed byaddition of methanesulfonyl chloride (0.47 g, 6.0 mmol) over 3 min. Thereaction mixture was stirred for 25 min and then N-acetyl-4-aminobutyricacid (1.6 g, 10.1 mmol) added. The reaction mixture was then heated atreflux for 18 h, cooled and washed with sat. NaHCO₃ (aq). The organicphase was dried over MgSO₄, filtered and evaporated. The residue wasfurther purified on silica eluting with 1:1:0.1 to 1:1:0.2dichloromethane/ethyl acetate/methanol to give the title compound as anoff white solid (1.1 g, 34%).

¹H NMR (CDCl₃, 300 MHz) δ 1.70-1.80 (m, 2H), 1.80-1.90 (m, 4H), 1.97 (s,3H), 2.41 (t, 2H), 2.50-2.57 (m, 2H), 2.60-2.75 (m, 6H), 2.83-2.88 (m,2H), 3.03-3.12 (m, 4H), 3.24-3.32 (m, 2H), 3.95-4.00 (m, 2H), 5.85-5.92(m, 3H), 6.58 (d, 2H), 6.92-6.96 (m, 1H), 7.05 (d, 1H), 7.12-7.16 (m,2H)) m/z (M⁺H) 605.08.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl4-octanamidobutanoate (Example 37: Compound 45)

Compound 149 (1.4 g) was synthesized in a similar manner to Compound148.

¹H NMR (d₆-DMSO, 300 MHz) δ 0.79 (t, 3H), 1.10-1.28 (m, 8H), 1.38-1.48(m, 2H), 1.50-1.77 (m, 6H), 1.93-2.00 (m, 2H), 2.25-2.40 (m, 4H),2.40-2.60 (m, 6H), 2.72-2.81 (m, 2H), 2.87-3.02 (m, 6H), 3.90-4.00 (m,2H), 5.82 (s, 2H), 6.58-6.63 (m, 2H), 7.04-7.02 (m, 2H), 7.20-7.30 (m,2H). m/z (M⁺H) 689.47.

(5-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloro-2-oxoindolin-1-yl)methylhexanoate (Example 38: Compound 322)

STEP 1: Thionyl chloride (12.31 g, 103 mmol) followed by catalyticamount of N,N-dimethyl formamide (DMF, 0.1 mL) was added to a solutionof Hexanoic acid (10 g, 86 mmol) in dichloromethane (DCM, 100 mL) at25-30° C. The reaction solution was stirred at same temperature for 2hours under nitrogen atmosphere, upon completion of the startingmaterial by TLC analysis. The volatiles were evaporated under reducedpressure below 40° C., which provided a viscous liquid material,hexanoyl chloride (about 10.5 g).

STEP 2: To the above hexanoyl chloride, para formaldehyde (3.8 g, 128mmol) and anhydrous ZnCl₂ (0.232 g, 17 mmol) were added at 25-30° C.under inert atmosphere and then heated to 90° C. The thick mass wasstirred at 90-95° C. for 5 hours, which after cooling provided crudeproduct, chloromethyl hexanoate which was purified by silica gel columnchromatography.

¹H-NMR (CDCl₃, 500 MHz): δ 5.70 (s, 2H), 2.39-2.33 (m, 2H), 1.69-1.61(m, 2H), 1.33-1.28 (m, 4H), 0.90-0.88 (t, J=7, 3H).

STEP 3: Chloromethyl hexanoate (3.18 g, 19.0 mmol) in dichloromethane (6mL) was added to a suspension of Ziprasidone free base (4.0 g, 9.6mmol), triethyl amine (4.0 mL, 27 mmol) and 4-dimethylamino pyridine(DMAP, 0.708 g, 5 mmol) in dichloride methane (240 mL) at 25-30° C. Thereaction solution was stirred for 24 h at same temperature. The crudemixture was washed with water (100 mL) followed by brine solution (100mL), upon solvent evaporation under vacuum below 40° C. provided crudetitle product, Compound 322, which was further purified by silica gelcolumn chromatography. (1.4 g, 27% yield)

¹H-NMR (CDCl₃, 500 MHz): δ 7.92-7.90 (d, J=7.5, 1H), 7.82-7.80 (d,J=7.5, 1H), 7.48-7.45 (t, J=7.5, 1H), 7.37-7.34 (t, J=7.5, 1H), 7.17 (s,1H), 7.05 (s, 1H), 5.72 (s, 2H), 3.60-3.55 (m, 6H), 2.98-2.95 (t, J=7.5,2H), 2.79-2.78 (m, 4H), 2.68-2.65 (t, J=8.5, 2H), 2.35-2.32 (t, J=7.5,2H), 1.64-1.61 (t, J=7.5, 2H), 1.29-1.25 (m, 4H), 0.88-0.85 (t, J=7,3H).

Mass (m/z)=541 [M⁺+1].

(5-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloro-2-oxoindolin-1-yl)methyldodecanoate (Example 39: Compound 324)

Compound 324 was synthesized in a similar manner to Compound 322,Example 38.

¹H-NMR (CDCl₃, 500 MHz): δ 7.92-7.90 (d, J=7.5, 1H), 7.82-7.80 (d,J=7.5, 1H), 7.48-7.45 (t, J=7.5, 1H), 7.37-7.34 (t, J=7.5, 1H), 7.17 (s,1H), 7.05 (s, 1H), 5.72 (s, 2H), 3.60-3.55 (m, 6H), 2.98-2.95 (t, J=8,2H), 2.79-2.77 (m, 4H), 2.68-2.65 (t, J=8, 2H), 2.34-2.31 (t, J=7, 2H),1.63-1.60 (m, 2H), 1.24 (s, 16H), 0.89-0.86 (t, J=7, 3H).

Mass (m/z)=625.5 [M⁺+1].

(5-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloro-2-oxoindolin-1-yl)methylpalmitate (Example 40: Compound 326)

¹H-NMR (CDCl₃, 500 MHz): δ 7.92-7.90 (d, J=7.5, 1H), 7.82-7.80 (d,J=7.5, 1H), 7.48-7.45 (t, J=7.5, 1H), 7.37-7.34 (t, J=7.5, 1H), 7.17 (s,1H), 7.05 (s, 1H), 5.72 (s, 2H), 3.60-3.55 (m, 6H), 2.98-2.95 (t, J=8,2H), 2.79-2.77 (m, 4H), 2.68-2.65 (t, J=8, 2H), 2.34-2.31 (t, J=8, 2H),1.63-1.56 (m, 2H), 1.25-1.23 (m, 24H), 0.88-0.86 (t, J=7, 2H).

Mass (m/z)=681.5 [M⁺+1].

(7-[(4-biphenyl-3ylmethyl)piperazin-1-yl]-2-oxobenzo[d]oxazol-3(2H)-yl)methyl acetate(Example 41: Compound 416)

Step 1: Synthesis of chloromethyl acetate: Acetyl chloride (5 g, 0.06mol) was added dropwise to a mixture of paraformaldehyde (8.5 g, 0.06mol) and anhydrous zinc chloride (0.175 g, 0.02 mol) at 0° C. underArgon. The reaction mixture was warmed to room temperature and stirredfor 1 hour, then heated to 90° C. for 18 hours. The solid was filteredoff washed with dichloromethane, and the filtrate was concentrated undervacuum at 37° C. to provide the desired product (6.6 g, 94% yield). Theproduct was used directly (without purification) in to next step andstored with activated molecular sieves (4° A).

Step 2: Synthesis of iodomethyl acetate: Sodium iodide (27.6 g, 0.18mol) was added to a solution of chloromethyl acetate (6.6 g, 0.06 mol)in acetonitrile (66 mL). The reaction flask was covered in aluminum foilto exclude light and stirred at ambient temperature for 15 hours. Thereaction mixture was partition between dichloromethane and water, andthe aqueous layer was extracted with dichloromethane. The combineorganics were washed with aqueous saturated NaHCO₃, 10% aqueous sodiumsulfite solution, and brine then dried with sodium sulphate andconcentrated to give the product (1.13 g, 12% yield) as a yellow oil.

Step 3: n-Butyl lithium (1.6 M in hexane; 3.8 mL, 0.007 mol) was addeddrop wise from a syringe to a stirred solution of bifeprunox (1.46 g,0.003 mol) in tetrahydrofuran at −78° C. After 1 hour a solution ofiodomethyl acetate (1.13 g, 0.005 mol) was added drop-wise at −70° C.The reaction mixture was stirred for 15 hours. The reaction mixture wasdumped in a saturated aqueous solution of ammonium chloride andextracted with ethyl acetate. The combined organic layers were washedwith 1N solution of NaOH and brine, then dried with sodium sulphate andconcentrated under vacuum. Purification by flash chromatography providedcompound 416. (0.25 g, 14% yield). ¹H NMR (DMSO, 400 MHz) δ 2.034 (s,3H), 2.565 (s, 4H), 3.183 (s, 4H), 3.597 (s, 2H), 5.765 (s, 2H),6.696-6.717 (d, 1H), 6.882-6.901 (d, 1H), 7.091-7.182 (t, 1H),7.315-7.370 (q, 2H), 7.404-7.473 (m, 3H), 7.515-7.555 (d, 1H), 7.59 (d,1H), 7.639-7.657 (d, 2H). m/z (M+H) 457.

(7-[(4-biphenyl-3ylmethyl)piperazin-1-yl]-2-oxobenzo[d]oxazol-3(2H)-yl)methyl butyrate(Example 42: Compound 417)

Compound 417 was prepared in a similar manner to Example 41 usingbutanoyl chloride. Purification by flash chromatography provided thedesired product (1.25 g, 45% yield). 1H NMR (DMSO, 400 MHz) δ 1.065 (t,3H), 1.448-1.54 (m, 2H), 2.284-2.320 (t, 2H), 2.564 (s, 4H), 3.184 (s,4H), 3.597 (s, 2H), 5.787 (s, 2H), 6.694-6.713 (d, 1H), 6.878-6.896 (d,1H), 7.092-7.133 (t, 1H), 7.315-7.370 (q, 2H), 7.422-7.533 (m, 3H),7.535-7.555 (d, 1H), 7.639 (d, 1H), 7.657-7.660 (d, 2H). m/z (M+H)₄₈₅.

(7-[(4-biphenyl-3ylmethyl)piperazin-1-yl]-2-oxobenzo[d]oxazol-3(2H)-yl)methyl hexanoate(Example 43: Compound 413)

Compound 413 was prepared in a similar manner to Example 41 usinghexanoyl chloride. Purification by flash chromatography provided thedesired product (0.6 g, 60% yield). 1H NMR (DMSO, 400 MHz) δ 0.774 (t,3H), 1.114-1.187 (m, 4H), 1.433-1.506 (m, 2H), 2.291-2.328 (t, 2H),2.564 (s, 4H), 3.182 (s, 4H), 3.597 (s, 2H), 5.783 (s, 2H), 6.693-6.713(d, 1H), 6.870-6.890 (d, 1H), 7.090-7.130 (t, 1H), 7.314-7.351 (q, 2H),7.422-7.472 (m, 3H), 7.535-7.554 (d, 1H), 7.589 (d, 1H), 7.638-7.656 (d,2H). m/z (M+H)₅₁₃.

(7-[(4-biphenyl-3ylmethyl)piperazin-1-yl]-2-oxobenzo[d]oxazol-3(2H)-yl)methyl palmitate(Example 44: Compound 422)

Compound 422 was prepared in a similar manner to Example 41 usingpalmitoyl chloride. Purification by flash chromatography provided thedesired product (0.5 g, 47% yield). 1H NMR (DMSO, 400 MHz) δ 0.819 (t,3H), 1.127-1.302 (m, 22H), 1.437-1.454 (t, 2H), 2.287-2.305 (t, 2H),2.564 (s, 4H), 3.182 (s, 4H), 3.596 (s, 2H), 5.784 (s, 2H), 6.688-6.708(d, 1H), 6.863-6.882 (d, 1H), 7.083-7.124 (t, 1H), 7.331-7.368 (q, 2H),7.400-7.470 (m, 3H), 7.534-7.553 (d, 1H), 7.587 (d, 1H), 7.635-7.653 (d,2H). m/z (M+H)₆₅₃.

(7-[(4-biphenyl-3ylmethyl)piperazin-1-yl]-2-oxobenzo[d]oxazol-3(2H)-yl)methyl decanoate(Example 45: Compound 419)

Compound 419 was prepared in a similar manner to Example 41 usingdecanoyl chloride. Purification by flash chromatography provided thedesired product (0.8 g, 77% yield). 1H NMR (DMSO, 400 MHz) δ 0.795-0.829(t, 3H), 1.140-1.211 (m, 12H), 1.438-1.471 (t, 2H), 2.288-2.324 (t, 2H),2.562 (s, 4H), 3.181 (s, 4H), 3.595 (s, 2H), 5.783 (s, 2H), 6.689-6.709(d, 1H), 6.856-6.884 (d, 1H), 7.083-7.124 (t, 1H), 7.311-7.367 (q, 2H),7.400-7.470 (m, 3H), 7.533-7.552 (d, 1H), 7.587 (d, 1H), 7.635-7.653 (d,2H). m/z (M+H) 569.

(7-[(4-biphenyl-3ylmethyl)piperazin-1-yl]-2-oxobenzo[d]oxazol-3(2H)-yl)methyl isobutyrate(Example 46: Compound 414)

Compound 414 was prepared in a similar manner to Example 41 usingisobutyryl chloride. Purification by flash chromatography provided thedesired product (0.3 g, 15% yield). 1H NMR (DMSO, 400 MHz) δ 1.027-1.044(d, 6H), 2.478-2.553 (m, 1H), 2.562 (s, 4H), 3.185 (s, 4H), 3.597 (s,2H), 5.785 (s, 2H), 6.692-6.713 (d, 1H), 6.873-6.892 (d, 1H),7.093-7.134 (t, 1H), 7.315-7.369 (q, 2H), 7.403-7.472 (m, 3H),7.533-7.555 (d, 1H), 7.590 (d, 1H), 7.657-7.660 (d, 2H). m/z (M+H)₄₈₅.

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methylbutyrate (Example 47: Compound 151)

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylbutyrate (Compound 2) was prepared as described in Example 16, supra.

To a stirred solution of(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylbutyrate (3.26 g, 5.94 mmol) in THF (100 mL) was added TFA (2.74 mL,35.63 mmol) followed by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ; 7.01g, 30.88 mmol) in THF (40 mL). The reaction was stirred at roomtemperature over the weekend. The reaction was quenched with water (100mL) and then poured into water (600 mL) and dichloromethane (100 mL).Solid NaHCO₃ (100 g) was added and the mixture stirred for approximately30 minutes. Dichloromethane (200 mL) was added and the mixture filtered.The collected filtrate was transferred to a separating funnel and thelayers separated. The aqueous layer was extracted with dichloromethane(2×100 mL) and the combined organics washed with water (3×100 mL, brine(100 mL) and dried over MgSO₄. After filtration, the volatiles wereremoved. The crude material was purified by silica chromatographyeluting 0-4% Methanol/(1:1 ethyl acetate/dichloromethane). The oil wasrecrystallized from methanol to give Compound 151. (2.03 g, 3.72 mmol,63% yield).

¹H-NMR (300 MHz, CDCl₃) δ 7.63 (1H, d), 7.45 (1H, d), 7.19-7.06 (2H, m),6.99-6.90 (1H, m), 6.88-6.78 (2H, m), 6.52 (1H, d), 6.33 (2H, s), 4.06(2H, t), 3.17-2.99 (4H, bs), 2.74-2.43 (6H, m), 2.35 (2H, t), 1.94-1.54(6H, m), 0.93 (3H, t).

The Following Compounds were Synthesized in a Similar Manner to Example47 from their Corresponding 3,4 Dihydro Precursors(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methylpalmitate (Example 48: Compound 159)

Compound 159 was synthesized in a similar manner to Example 47 fromCompound 10. 2.04 g. ¹H-NMR (400 MHz, CDCl₃) δ 7.62 (1H, d), 7.44 (1H,d), 7.18-7.10 (2H, m), 6.98-6.91 (1H, m), 6.87-6.80 (2H, m), 6.52 (1H,d), 6.32 (2H, s), 4.05 (2H, t), 3.15-2.99 (4H, bs), 2.74-2.44 (6H, m),2.35 (2H, t), 1.92-1.83 (2H, m), 1.80-1.68 (2H, m) 1.66-1.55 (2H, m),1.32-1.14 (24H, m), 0.87 (3H, t).

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyllaurate (Example 49: Compound 156)

Compound 156 was synthesized in a similar manner to Example 47 fromCompound 7. 1.37 g. ¹H-NMR (400 MHz, CDCl₃) δ 7.62 (1H, d), 7.43 (1H,d), 7.17-7.10 (2H, m), 6.96-6.92 (1H, m), 6.87-6.80 (2H, m), 6.51 (1H,d), 6.33 (2H, s), 4.06 (2H, t), 3.12-3.01 (4H, bs), 2.71-2.59 (4H, bs),2.50 (2H, t), 2.35 (2H, t), 1.92-1.83 (2H, m), 1.78-1.69 (2H, m)1.66-1.55 (2H, m), 1.32-1.16 (16H, m), 0.86 (3H, t).

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methylstearate (Example 50: Compound 160)

Compound 160 was synthesized in a similar manner to Example 47 fromCompound 11. 1.38 g¹H-NMR (400 MHz, CDCl₃) δ 7.62 (1H, d), 7.44 (1H, d),7.17-7.11 (2H, m), 6.97-6.92 (1H, m), 6.87-6.79 (2H, m), 6.51 (1H, d),6.32 (2H, s), 4.05 (2H, t), 3.13-3.00 (4H, bs), 2.73-2.58 (4H, bs), 2.50(2H, t), 2.35 (2H, t), 1.92-1.83 (2H, m), 1.79-1.69 (2H, m) 1.66-1.55(2H, m), 1.32-1.14 (28H, m), 0.87 (3H, t).

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methylacetate (Example 51: Compound 150)

Compound 150 was synthesized in a similar manner to Example 47 fromCompound 1. 1.61 g¹H-NMR (300 MHz, CDCl₃) δ 7.63 (1H, d), 7.45 (1H, d),7.18-7.11 (2H, m), 6.98-6.92 (1H, m), 6.90-6.80 (2H, m), 6.52 (1H, d),6.32 (2H, s), 4.07 (2H, t), 3.14-3.01 (4H, bs), 2.73-2.59 (4H, bs), 2.51(2H, t), 2.12 (3H, s), 1.95-1.82 (2H, m), 1.82-1.68 (2H, m).

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl2,2-dimethylbutanoate (Example 52: Compound 165)

Compound 165 was synthesized in a similar manner to Example 47 fromCompound 16. 1.02 g¹H-NMR (400 MHz, CDCl₃) δ 7.61 (1H, d), 7.43 (1H, d),7.17-7.10 (2H, m), 6.97-6.92 (1H, m), 6.83-6.79 (2H, m), 6.51 (1H, d),6.31 (2H, s), 4.05 (2H, t), 3.12-3.02 (4H, bs), 2.71-2.60 (4H, bs), 2.50(2H, t), 1.92-1.83 (2H, m), 1.78-1.68 (2H, m) 1.55 (2H, q), 1.15 (6H,s), 0.81 (3H, t).

(2-(N-(1-(1-(4-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-N-methylamino)-6-oxopyrimidin-1(6H)-yl)methyloctanoate (Example 53: Compound 704)

Step 1:

Octanoyl chloride (10 g, 0.06 mol) was added drop wise to a mixture ofparaformaldehyde (8.07 g, 0.06 mol) and anhydrous zinc chloride (0.163g, 0.0012 mol) at 0° C. under Argon. After the addition was completed,the reaction mixture was stirred at 25° C. for 1 hour, and then heatedto 90° C. for 16 hours. The solid was filtered off and washed withdichloromethane. The filtrate was concentrated in vacuo at 37° C. toprovide the desired chloromethyl octanoate (9.5 g, 84% yield), which wasused directly (without purification) in the next step. This product wasstored over activated molecular sieves (4° A) to keep it dry.

Step 2:

Sodium iodide (21.7 g, 0.1449 mol) was added to a solution ofchloromethyl octanoate (9.5 g, 0.0483 mol) in of acetonitrile (100 ml).The flask was covered in aluminum foil to protect from light and stirredat 25° C. for 16 hours. The reaction mixture was partitioned betweendichloromethane and water the aqueous layer was further extracted withdichloromethane. The combined organic extracts were washed with aqueoussaturated NaHCO₃, 10% aqueous sodium sulfite solution and brine, andfinally dried with sodium sulphate and concentrated in vacuo to providethe product (8.4 g, 71% yield) as a yellow oil. This product was takeninto the next step without further purification.

Step 3:

n-Butyl lithium (1.5 M in hexane; 14.6 ml, 0.0042 mol) was added dropwise to a stirred solution of2-(N-(1-(1-(4-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-N-methylamino)pyrimidin-4(3H)-one(Mizolastine, 14.3 g, 0.00696 mol) in tetrahydrofuran (50 ml) at −78° C.After 1 hour the reaction mixture was treated drop-wise with aiodomethyl octanoate (2.5 g, 0.0231 mol) at −70° C. The reaction mixturewas stirred at 25° C. for 16 hours. The reaction mixture was poured intoammonium chloride solution and extracted with ethyl acetate. Thecombined organic was washed with aqueous sodium hydroxide (1N) andbrine, and then dried with sodium sulphate and concentrated in vacuo.Flash chromatography provided the desired product (0.45 g, 17% yield).

¹H NMR (DMSO, 400 MHz) δ 0.815 (t, 3H), 1.117-1.235 (m, 10H),1.474-1.491 (t, 2H), 1.638-1.665 (d, 2H), 1.992-2.010 (m, 2H),2.292-2.230 (t, 2H), 2.992 (s, 3H), 3.027-3.088 (t, 2H), 3.55-3.62 (t,2H), 4.625 (s, 1H) 5.311 (s, 2H), 6.040 (s, 2H), 6.110-6.124 (d, 1H),7.014-7.076 (m, 2H), 7.148-7.253 (m, 5H), 7.442-7.460 (d, 1H),8.187-8.201 (d, 1H). m/z (M⁺H) 589.

(2-(N-(1-(1-(4-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-N-methylamino)-6-oxopyrimidin-1(6H)-yl)methyllaurate (Example 54: Compound 706)

Compound 706 was synthesized using a similar procedure as Example 53using lauroyl chloride.

¹H NMR (DMSO, 400 MHz) δ 0.791-0.826 (t, 3H), 1.134-1.210 (m, 16H),1.446 (t, 2H), 1.642-1.925 (d, 2H), 1.956-2.008 (m, 2H), 2.266-2.301 (t,2H), 2.968 (s, 3H), 3.003-3.063 (t, 2H), 3.31-3.62 (t, 2H), 4.625 (s,1H) 5.286 (s, 2H), 6.015 (s, 2H), 6.085-6.099 (d, 1H), 7.015-7.072 (m,2H), 7.122-7.215 (m, 5H), 7.418-7.436 (d, 1H), 8.159-8.172 (d, 1H). m/z(M⁺H) 645.5.

(5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)-2,4-dioxothiazolidin-3-yl)methylhexanoate (Example 55: Compound 1003)

Step 1: Chloromethyl hexanoate was synthesized from hexanoyl chloride ina similar process as described above in Example 53, step 1.

Step 2: Iodomethyl hexanoate was synthesized from chloromethyl hexanoatein a similar process as described above in Example 53, step 2.

Step 3: A solution of Pioglitazone (3.0 g, 0.0084 mol) in dimethylformamide was treated with dry K₂CO₃ (3.48 g, 0.0252) at 25° C. After 40minutes a solution of Iodomethyl hexanoate (4.29 g, 0.0168 mol) wasadded drop-wise. The reaction mixture was stirred for 15 hours, thendumped into water and extracted with ethyl acetate. The combined organiclayers were dried with sodium sulphate and concentrated under vacuum.The product was purified by flash chromatography to obtain the desiredproduct (1.9 g, 44% yield).

¹H NMR (CDCl₃, 400 MHz) δ 0.86-0.90 (t, 3H), 1.22-1.29 (m, 8H),1.58-1.62 (t, 2H), 2.27-2.31 (t, 2H), 2.62-2.64 (d, 2H), 3.04-3.099 (q,1H), 3.21-3.25 (t, 2H), 3.452-3.497 (q, 1H), 4.30-4.34 (t, 2H),4.46-4.48 (d, 1H), 5.513-5.51 (d, 2H), 6.81-6.85 (t, 2H), 7.09-7.11 (d,2H), 7.18-7.20 (d, 1H), 7.46-7.48 (q, 1H), 8.38-8.39 (d, 1H) m/z (M⁺H)485.

(5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)-2,4-dioxothiazolidin-3-yl)methyllaurate (Example 56: Compound 1006)

Compound 1006 was synthesized using a similar procedure as Example 55using lauroyl chloride.

¹H NMR (CDCl₃, 400 MHz) δ 0.802-0.836 (t, 3H), 1.133-1.171 (t, 4H),1.197-1.235 (d, 15H), 1.308 (s, 1H), 1.419-1.452 (t, 2H), 2.172.254 (q,2H), 2.533-2.590 (q, 2H), 3.044-3.118 (m, 3H), 4.251-4.284 (t, 2H),4.97-5.005 (q, 1H), 5.345-5.413 (q, 2H), 6.82-6.841 (d, 2H), 7.09-7.11(d, 2H), 7.23-7.25 (d, 1H), 7.53-7.55 (q, 1H), 8.33-8.34 (d, 1H) m/z(M⁺H) 569.

(5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)-2,4-dioxothiazolidin-3-yl)methylpalmitoate (Example 57: Compound 1008)

Compound 1008 was synthesized using a similar procedure as Example 55using palmitoyl chloride.

¹H NMR (CDCl₃, 400 MHz) δ 0.870 (s, 3H), 1.23-1.26 (t, 27H), 1.57-1.61(t, 2H), 2.27-2.31 (t, 2H), 2.61.265 (t, 2H), 3.06-310 (t, 1H),3.22-3.25 (t, 2H), 3.45-3.46 (d, 1H), 4.31-4.34 (t, 2H), 4.45-4.49 (q,1H), 5.487-5.541 (q, 2H), 6.83-6.85 (d, 2H), 7.09-7.11 (d, 2H),7.19-7.26 (t, 1H), 7.47-7.49 (q, 1H), 8.393-8.397 (d, 1H) m/z (M⁺H) 625.

(5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)-2,4-dioxothiazolidin-3-yl)methylstearoate (Example 58: Compound 1009)

Compound 1009 was synthesized using a similar procedure as Example 55using stearoyl chloride.

¹H NMR (CDCl₃, 400 MHz) δ 0.874-0.894 (t, 3H), 1.222-1.260 (t, 30H),1.570-1.603 (d, 1H), 2.27-2.31 (t, 2H), 2.609-2.266 (q, 2H), 3.04-3.10(q, 1H), 3.20-3.24 (t, 2H), 3.46-3.50 (q, 1H), 4.302-4.335 (t, 2H),4.453-4.487 (q, 1H), 5.488-5.552 (q, 2H), 6.83-6.86 (d, 2H), 7.09-7.11(d, 2H), 7.17-7.19 (d, 1H), 7.44-7.47 (d, 1H), 8.386-8.391 (d, 1H) m/z(M⁺H) 653.

(5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)-2,4-dioxothiazolidin-3-yl)methylmyristoate (Example 59: Compound 1007)

Compound 1007 was synthesized using a similar procedure as Example 55using myristoyl chloride.

¹H NMR (CDCl₃, 400 MHz) δ 0.854-0.887 (t, 3H), 1.226-1.262 (t, 24H),1.57-1.604 (t, 2H), 2.27-2.308 (t, 2H), 2.609-2.265 (t, 2H), 3.035-3.094(q, 1H), 3.223-3.256 (t, 2H), 3.456-3.500 (q, 1H), 4.307-4.340 (t, 2H),4.463-4.487 (t, 1H), 5.487-5.540 (q, 2H), 6.832-6.852 (d, 2H),7.092-7.114 (d, 2H), 7.198-7.217 (d, 1H), 7.475-7.491 (d, 1H),8.393-8.397 (d, 1H) m/z (M⁺H) 596.

(5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)-2,4-dioxothiazolidin-3-yl)methylbutyrate (Example 60: Compound 1002)

Compound 1002 was synthesized using a similar procedure as Example 55using butyroyl chloride.

¹H NMR (CDCl₃, 400 MHz) δ 0.798-0.835 (t, 3H), 1.133-1.212 (q, 4H),1.417-1.509 (m, 2H), 2.210-2.246 (t, 2H), 2.482-2.2591 (q, 2H),3.047-3.118 (q, 3H), 4.253-4.286 (t, 2H), 4.983-5.016 (q, 1H),5.353-5.415 (q, 2H), 6.824-6.845 (d, 2H), 7.097-7.118 (d, 2H),7.239-7.258 (d, 1H), 7.538-7.563 (d, 1H), 8.340-8.365 (d, 1H) m/z (M⁺H)458.

(5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)-2,4-dioxothiazolidin-3-yl)methylcyclohexanecarboxylate (Example 60: Compound 1015)

Compound 1015 was synthesized using a similar procedure as Example 55using cyclohexanecarbonyl chloride.

¹H NMR (CDCl₃, 400 MHz) δ 1.181-1.293 (m, 7H), 1.359-1.449 (m, 2H),2.624 (s, 1H), 1.714-1.738 (t, 2H), 1.843-1.874 (q, 2H), 2.244-2.319 (m,1H), 2.607-2.664 (q, 2H), 3.049-3.107 (q, 1H), 3.22.-3.253 (t, 2H),3.340-3.485 (q, 1H), 5.481-5.534 (q, 2H), 6.831-6.853 (d, 2H),7.091-7.113 (d, 2H), 7.193-7.213 (d, 1H), 7.465-7.590 (q, 1H),8.392-8.396 (d, 1H) m/z (M⁺H) 497.

General Scheme for Synthesis

((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl)oxy)methylhexyl carbonate (Example 61: Compound 1240)

To a solution of dehydro-Aripiprazole (1.5 g, 3.36 mmol) in2-methyltetrahydrofuran (30 mL) was added silver carbonate (1.853 g,6.72 mmol) and hexyl iodomethyl carbonate (2.021 g, 7.05 mmol) in2-methyltetrahydrofuran (4 mL) at room temperature. The reaction wasstirred for 4.5 days. The reaction was quenched with H₂O (30 mL) andfiltered through celite. The reaction was extracted with ethyl acetate(3×20 mL), washed with brine (20 mL), dried over MgSO₄ and concentrated.The product was purified by column chromatography on silica eluting with1:1 ethyl acetate to dichloromethane to 2% MeOH in 1:1 ethyl acetate todichloromethane to provide Compound-1240 (1.08 g) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.96 (1H, d), 7.60 (1H, d), 7.21 (1H, m), 7.14(2H, m), 7.03 (1H, dd), 6.94 (1H, m), 6.81 (1H, d), 6.26 (2H, s), 4.18(2H, m), 4.12 (2H, t), 3.09 (4H, m), 2.68 (4H, m), 2.53 (2H, m), 1.91(2H, m), 1.78 (2H, m), 1.63 (2H, m), 1.28 (6H, m), 0.86 (3H, t).[M+H]⁺=604.2

((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl)oxy)methyloctanoate (Example 62: Compound 1206)

To a solution of dehydro-Aripiprazole (1.0 g, 2.24 mmol) in2-methyltetrahydrofuran (25 mL) was added silver carbonate (0.864 g,3.13 mmol) and iodomethyl octanoate (0.764 g, 2.68 mmol) at roomtemperature. The reaction was stirred for 5 days. The reaction wasquenched with H₂O (30 mL) and filtered through celite. The reaction wasextracted with ethyl acetate (3×20 mL), washed with 5% w/v sodiumsulfite solution (15 mL), brine (20 mL), dried over MgSO₄ andconcentrated. The product was purified by column chromatography onsilica eluting with 0-70% ethyl acetate in heptane to provide Compound1206 (0.602 g) as a pale orange oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.95 (1H, d), 7.60 (1H, d), 7.21 (1H, m), 7.14(2H, m), 7.07 (1H, dd), 6.95 (1H, m), 6.79 (1H, d), 6.24 (2H, s), 4.12(2H, m), 3.09 (4H, m), 2.68 (4H, m), 2.54 (2H, m), 2.36 (2H, t), 1.90(2H, m), 1.77 (2H, m), 1.61 (4H, m), 1.23 (6H, m), 0.83 (3H, t).[M+H]⁺=602.2.

((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl)oxy)methyldodecanoate (Example 63: Compound 1208)

The experimental procedure was carried out in the same manner as forCompound-1206 in Example 62, to give 1208 (0.738 g) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.95 (1H, d), 7.60 (1H, d), 7.20 (1H, d), 7.14(2H, m), 7.05 (1H, dd), 6.95 (1H, m), 6.80 (1H, d), 6.24 (2H, s), 4.13(2H, m), 3.09 (4H, m), 2.68 (4H, m), 2.54 (2H, m), 2.36 (2H, t), 1.93(2H, m), 1.80 (2H, m), 1.60 (4H, m), 1.23 (14H, m), 0.86 (3H, t).[M+H]⁺=658.4.

((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl)oxy)methylbutyrate (Example 64: Compound 1202)

The experimental procedure was carried out in the same manner as forCompound-1206 in Example 62, to give 1202 (0.695 g) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.95 (1H, d), 7.61 (1H, d), 7.20 (1H, d), 7.14(2H, m), 7.04 (1H, dd), 6.96 (1H, m), 6.79 (1H, d), 6.25 (2H, s), 4.13(2H, m), 3.09 (4H, m), 2.69 (4H, m), 2.54 (2H, m), 2.35 (2H, t), 1.91(2H, m), 1.78 (2H, m), 1.66 (2H, m), 0.94 (3H, t). [M+H]⁺=546.1.

Example 65:((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl)oxy)methyl2,2-dimethyltetradecanoate (Compound 1213) and(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl2,2-dimethyltetradecanoate (Compound 255)

The experimental procedure was carried out in the same manner as forCompound-1206 in Example 62 to give both Compound-255 and Compound-1212.Compound-1213 was isolated (0.586 g) as a yellow oil, and Compound-255was isolated (0.156 g) as a yellow oil.

Compound-1213: ¹H-NMR (300 MHz, CDCl₃) δ 7.93 (1H, d), 7.59 (1H, d),7.16 (3H, m), 7.03 (1H, dd), 6.97 (1H, m), 6.78 (1H, d), 6.22 (2H, s),4.12 (2H, m), 3.10 (4H, m), 2.73 (4H, m), 2.57 (2H, t), 1.91 (2H, m),1.80 (2H, m), 1.46 (2H, d), 1.01-1.33 (26H, m), 0.87 (3H, t).[M+H]⁺=714.3.

Compound-255: ¹H-NMR (300 MHz, CDCl₃) δ 7.60 (1H, d), 7.42 (1H, d), 7.15(2H, m), 6.96 (1H, m), 6.82 (2H, m), 6.51 (1H, d), 6.32 (2H, s), 4.04(2H, t), 3.07 (4H, m), 2.66 (4H, m), 2.49 (2H, m), 1.87 (2H, m), 1.76(2H, m), 1.45 (2H, m), 1.01-1.36 (26H, m), 0.87 (3H, t). [M+H]⁺=714.3.

((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl)oxy)methyldiethylcarbamate (Example 66: Compound 1247)

The experimental procedure was carried out in the same manner as forCompound-1206 in Example 62. The reaction was incomplete after 5 days atroom temperature. The reaction was heated to 60° C. for two days beforefollowing the same work-up and purification procedures as in Example-62to give Compound-1247 (0.053 g) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.94 (1H, d), 7.60 (1H, d), 7.20 (1H, m), 7.15(2H, m), 7.04 (1H, dd), 6.95 (1H, m), 6.81 (1H, d), 6.24 (2H, s), 4.11(2H, m), 3.28 (4H, m), 3.09 (4H, m), 2.70 (4H, m), 2.54 (2H, m), 1.90(2H, m), 1.78 (2H, m), 1.13 (3H, q), 1.03 (3H, q). [M+H]⁺=575.2.

((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl)oxy)methylpivalate (Example 67: Compound 1215)

The experimental procedure was carried out in the same manner as forCompound-1206 in Example-62 to give Compound 1215 (0.555 g) as a yellowoil.

¹H-NMR (300 MHz, CDCl₃) δ 7.95 (1H, d), 7.60 (1H, d), 7.15 (3H, m), 7.05(1H, dd), 6.97 (1H, m), 6.79 (1H, d), 6.22 (2H, s), 4.12 (2H, m), 3.10(4H, m), 2.68 (4H, m), 2.54 (2H, m), 1.91 (2H, m), 1.78 (2H, m), 1.19(9H, s). [M+H]⁺=560.1.

Example 68: Pharmacokinetic Evaluation in Rats

Pharmacokinetic Evaluation of Prodrugs in Rats Following IntramuscularInjection

Animals:

Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass.)were obtained. Approximately 24 rats were used in each study. Rats wereapproximately 350-375 g at time of arrival. Rats were housed 2 per cagewith ad libitum chow and water. Environmental conditions in the housingroom: 64-67° F., 30% to 70% relative humidity, and 12:12-h light:darkcycle. All experiments were approved by the institutional animal careand use committee.

Pharmacokinetics Study:

Rats were dosed IM by means of a 25 gauge, ⅝ inch needle with 1 ccsyringe 0.3 mL suspension was withdrawn from the vial containing thetest compound (see Table E). The mouse was injected in the muscles ofthe hind limb after anesthesia with isoflourane. Blood samples werecollected via a lateral tail vein after brief anesthesia withIsoflurane. A 27½G needle and 1 cc syringe without an anticoagulant wasused for the blood collection. Approximately 350 μL of whole blood wascollected at each sampling time-point of 6 hours, 24 hours and 2, 5, 7,9, 12, 14, 21, 28, 35 days after administration. Once collected, wholeblood was immediately transferred to tubes containing K2 EDTA, inverted10-15 times and immediately placed on ice. The tubes were centrifugedfor 2 minutes at >14,000 g's (11500 RPMs using Eppendorf Centrifuge5417C, F45-30-11 rotor) at room temperature to separate plasma. Plasmasamples were transferred to labeled plain tubes (MICROTAINER®) andstored frozen at <−70° C.

Data Analysis:

Drug concentrations in plasma samples were analyzed by liquidchromatography-mass spectroscopy using appropriate parameters for eachcompound. Half-life, volume of distribution, clearance, maximalconcentration, and AUC were calculated by using WinNonlin Version5.2_software (Pharsight, St. Louis, Mo.).

Results and Discussion:

The Results are shown in Table J. As shown in Table J, each of thecompounds tested provides a plasma concentration that is extended ascompared to the parent drug when administered alone.

TABLE J API Form used (Compound Dose** AUC₀₋₁₄ AUC_(0-T) No.) Excipients(mg/kg) (ng * day/mL) (ng * day/mL) 82 solution in ethyl oleate 57 204NC 2 Recrystallized 67 1016.9 1139.8 crystalline suspension in 1% HPMCin PBS + 0.2% Tween 20 81 solution in ethyl oleate 56 584 NC 48 Milledcrystalline 70.00 2238 2264.6 suspension in 1% HPMC in PBS + 0.2% Tween20. Measured and diluted to correct concentration* 5 Ethyl oleateemulsion in 67 1728.6 1742 water with DPPC, Glycerol and NCOH 6 solutionin ethyl oleate 67 67 327 6 Oil emulsion in water 67 1490.3 1678.1 withDPPC and Glycerol 47 Milled crystalline 100.0 113 176 suspension in 1%HPMC 85 Milled crystalline 67 1233.9 1348 suspension in 1% HPMC in PBS +0.2% Tween 20. Measured and diluted to correct concentration 1Crystalline material 56.7 1673 1938 suspended in 1% HPMC 7Recrystallized 67 512.0 1169.5 crystalline suspention in 1% HPMC inPBS + 0.2% Tween 20 32 Milled crystalline 67 1334.4 1486 suspension in1% HPMC in PBS + 0.2% Tween 20. Measured and diluted to correctconcentration* 8 Milled crystalline 24 580.3 666.1 suspention in 1% HPMCin PBS + 0.2% Tween 20 49 Milled crystalline 73.3 152 199.7 suspensionin 1% HPMC 34 Milled crystalline 43.33 2050 2095.8 suspension in 1% HPMCin PBS + 0.2% Tween 20. Measured and diluted to correct concentration*79 Prodrug solution in ethyl 67 954 NC oleate 79 Recrystallized 67 907.4940 crystalline suspension in 1% HPMC in PBS + 0.2% Tween 20 31Recrystallized 67 819.0 997 crystalline suspension in 1% HPMC in PBS +0.2% Tween 20 10 Recrystallized 67 302 786.6 crystalline suspension in1% HPMC in PBS + 0.2% Tween 20 4 Recrystallized 67 1455.4 1678crystalline suspension in 1% HPMC in PBS + 0.2% Tween 20 1002Crystalline material in 67 5350 5972 2% CMC, 0.2% Tween 20, PBS buffer302 mOsm/Kg, pH 6.7 1008 Crystalline material in 67 5000 6763 2% CMC,0.2% Tween 20, PBS buffer 302 mOsm/Kg, pH 6.7

Example 69: Pharmacokinetic Study for Pioglitazone, Compounds 1002 and1008

PK profile of compounds 1002 and 1008 was compared to pioglitazone usinga similar model as described above. 20 mg of pioglitazone or 20 mgequilant of pioglitazone prodrug was administered intramuscularly. Theresults are tabulated in Table J, supra. FIG. 10 shows the PK profileand comparison with pioglitazone.

Example 70: Pharmacodynamic Studies Using an Amphetamine-InducedLocomotion Model

Introduction:

Prodrugs of the invention useful in the treatment of schizophrenia andbipolar disorder show predictive validity in rodent models ofhyperlocomotion. D-Amphetamine-induced locomotion is postulated to mimicthe dopaminergic hyperactivity which forms the basis for the “dopaminehypothesis” of schizophrenia. The AMPH-induced hyperactivity modelprovides a simple, initial screen of antipsychotic compound efficacy.See, Fell et al., Journal of Pharmacology and Experimental Therapeutics(2008) 326:209-217. Amphetamine induced hyperactivity was used to screenvarious doses of orally administered (PO) prodrug formulations ofaripiprazole to measure pharmacodynamic efficacy in an acutehyperlocomotion paradigm. The hypothesis of the study is that POadministration of aripiprazole prodrug formulations, which result inplasma concentrations of ˜100-200 ng/ml, will produce a significantattenuation of AMPH-induced locomotion.

General behavior and activity can be measured in experimental animals(typically rats and mice) in order to assess psychomotor stimulantproperties, anxiogenic/anxiolytic or sedative properties of a drug. Assuch, open-field studies can provide insight into the behavioral effectsof test compounds. Certain prodrugs of the present invention are usefulin the treatment of schizophrenia and bipolar disorder. Aripiprazole isa parent lactam containing drug from which some of the prodrugs of theinvention are derived that is useful in the treatment of schizophreniaand bipolar disorder. Such aripiprazole prodrugs of the invention showpredictive validity in rodent models of hyperlocomotion.D-Amphetamine-induced locomotion is postulated to mimic the dopaminergichyperactivity which forms the basis for the “dopamine hypothesis” ofschizophrenia. Likewise, glutamate NMDA receptor antagonist (MK-801,PCP, etc.) induced locomotion is postulated to mimic the NMDAhypoactivity hypothesis of schizophrenia (Fell et al., supra). Thesetests of drug-induced hyperactivity provide simple, initial screens ofantipsychotic compound efficacy. Amphetamine induced hyperactivity willbe used to screen various prodrugs of aripiprazole, administered PO inoil solutions, to measure pharmacodynamic efficacy. The results of theD-AMPH induced locomotion done in this study will be compared to thehistorical results of subcutaneous (S.C.) aripiprazole administration onD-AMPH. The hypothesis of the study is that PO exposure to aripiprazoleprodrugs, which results in aripiprazole concentrations of 100-200 ng/mlat locomotor testing, will display efficacy in in-vivo measures ofantipsychotic efficacy.

Materials:

Experimental Animals:

12, Sprague Dawley rats were purchased from Charles River Laboratory.The rats were approximately 90 days old, and weighed in the range of350-275 grams upon receipt from the supplier. One rat was placed in acage and allowed to acclimate for about 1 week. The rats were providedwith food and water ad libitum.

Dosing Solution of D-Amphetamine (D-AMPH):

D-AMPH was purchased from Sigma Aldrich. D-amphetamine HCl was preparedin 0.9% saline to a concentration of 1.5 mg/ml. D-Amphetamine was givenI.P. per body weight at a dose of 1 ml/kg (=1.5 mg/kg). Salt formcorrection was not used in accordance with historical literature.D-Amphetamine was prepared fresh from solid form 30 min. prior to eachtest period.

Dosing Solutions of Prodrug Derivatives of Aripiprazole:

TABLE K Dose Study Dose volume Group Formulation (Route) mg/rat mL N ACompound-7 oral oil 7.5 1.5 4 Solution (PO) B Compound-4 oral oil 20 1.54 Solution (PO) C Compound-4 oral oil 10 1.5 4 Solution (PO) DCompound-7 oral oil 10 1.5 4 Solution (PO) E Compound-4 oral oil 0.661.5 4 Solution (PO) F Compound-7 oral oil 20 1.5 4 Solution (PO) GSaline (PO) 0 1.5 4

Behavior Box:

The behavior chambers were purchased from Med Associates, Inc. of St.Albans, Vt., Model ENV-515. Software for measuring animal movement isprovided with the behavior chamber by the supplier.

Methods:

Following 1 week habituation to the animal facility, the activityassessments commenced. The animals were initially acclimated to thebehavior box for about 15 minutes before they were removed from the boxand injected PO with 1.5 ml of an aripiprazole prodrug compound of theinvention, at concentrations which produce PK levels of 100-200 ng/mlapproximately 1 hour after administration. After an additional 15minutes the animals were placed back in the behavior box for anadditional 30 minute drug-baseline test session. The mice were thenadministered by IP injection, D-AMPH (1.5 mg/kg) followed by a 60 minuteexperimental behavioral measurement period. The parameters that weremeasured were a) total distance measured (primary measure), b) totalnumber of ambulatory moves (second measure), c) total number of verticalmoves (secondary measure) and d) time spent immobile (secondarymeasure).

Blood Sampling:

Tail vein blood was taken on experiment days immediately followinglocomotor activity measurements (2-hours post-prodrug administration)and again the following day a time-point corresponding to 22 hourspost-prodrug administration. Blood samples were collected via a lateraltail vein after anesthesia with Isoflurane. A 27½ G syringe without ananticoagulant was used for the blood collection, and the whole bloodtransferred to pre-chilled (wet ice) tubes containing K2 EDTA. 0.5 ml ofblood per animal was collected per time point. The tubes were inverted15-20 times and immediately returned to the wet ice until beingcentrifuged for 2 minutes≥14,000 g to separate plasma. The plasmasamples prepared in this manner were transferred to labeled plain tubes(MICROTAINER®) and stored frozen at <−70° C.

Behavioral Data Acquisition:

Behavioral data was captured electronically by the software packageassociated with the behavior chambers. Data was transformed and analyzedvia GRAPHPAD PRISM® 5 software (GraphPad Software, Inc., La Jolla,Calif.). The data was analyzed using a 2-way repeated measures ANOVA.

Results and Discussion:

The results are shown in FIGS. 6 and 7. The results indicate that orallyadministered D-AMPH caused a significant increase in the total distancetraveled by the mice as compared to mice who were administered onlysaline. The results also indicate that aripiprazole prodrug compound 4of the invention significantly inhibited the increases in distancetraveled caused by D-AMPH. The inhibition of distance traveled bycompound 4 did not appear to be dose dependent. Likewise, aripiprazoleprodrug compounds 7 and 47 did appear to significantly inhibit increasesin distance traveled caused by D-AMPH at the higher dose of 20 mg. Thisdata indicates that in accordance with the invention, the prodrugcompounds are cleaved in vivo to release the parent drug (aripiprazolein this example) to provide the expected pharmacological effects on theanimal.

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound of formula XV and pharmaceuticallyacceptable salts and solvates thereof:

wherein each R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ is independently selectedfrom hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, optionally substitutedaliphatic, optionally substituted aryl or aryl or optionally substitutedheterocyclyl; alternatively, two or more R₅₀, R₅₁, R₅₂, R₅₃, and R₅₄together with the atoms to which they are attached form an optionallysubstituted ring; each R₁₀ and R₁₁ is independently absent, hydrogen,halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;alternatively two R₁₀ and R₁₁ together with the atoms to which they areattached may form an additional optionally substituted, 3, 4, 5, 6 or 7membered ring; wherein the term “substituted” refers to the replacementof one or more hydrogen radicals in a given structure with the radicalof a specified substituent selected from halo, alkyl, alkenyl, alkynyl,aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, heteroaryl,and aliphatic; R₁ is selected from:


2. A compound of claim 1 or a pharmaceutically acceptable salt orsolvate thereof, selected from:

or a pharmaceutically acceptable salt thereof.
 3. A compound of claim 1or a pharmaceutically acceptable salt thereof, wherein R₁ is selectedfrom:


4. A compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R₁ is selected from:


5. A compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R₁ is selected from:


6. A compound of claim 2, or a pharmaceutically acceptable salt thereof,wherein R₁ is selected from:


7. A compound of claim 2, or a pharmaceutically acceptable salt thereof,wherein R₁ is selected from:


8. A compound of claim 2, or a pharmaceutically acceptable salt thereof,wherein R₁ is selected from: